Methods of determining pharmacodynamic activity and treatment efficacy

Abstract

Disclosed are methods for determining the pharmacodynamic activity of one or more compounds by measurement of focal accumulation of CIP2A. Further disclosed are methods of determining the effectiveness of a treatment with one or more compounds b measurement of focal accumulation of CIP2A. Compounds of the invention may be Polθ kinase inhibitors or PARP inhibitors.

Description

[0001]PATENT ATTORNEY DOCKET: 51246-065WO2 METHODS OF DETERMINING PHARMACODYNAMIC ACTIVITY AND TREATMENT EFFICACY Field of the Invention The invention relates to compounds and pharmaceutical compositions, their preparation and 5 their use in the treatment of a disease or condition, e.g., cancer, and, in particular, those diseases or conditions (e.g., cancers) which are dependent on the activity of human Polymerase Theta (Polθ) and / or have high cellular MMEJ / Theta mediated repair or Alternative End-joining repair. Background 10 DNA damage occurs continually in cells as a result of environmental insults including ultraviolet radiation, X-rays, and endogenous stress factors, such as reactive oxygen and replicative stress. Cancer cells, in particular, are subject to a higher rate of DNA damage as a consequence of dysregulated DNA replication or as a consequence of anti-cancer therapy including irradiation or chemotherapy. Several DNA damage response pathways have evolved in a highly coordinated 15 manner to help repair DNA damage and to act as a cellular checkpoint to stop the replication of cells with damaged DNA, allowing for repair functions to occur before the damaged DNA is passed on to daughter cells. Each of the identified DNA repair pathways sense and repair distinct but overlapping types of DNA damage. Double-strand breaks (DSBs), in which both strands in the double helix are severed, are particularly deleterious to the cell because they can lead to genome rearrangement and 20 cell death. DSBs are repaired by homologous recombination (HR), classical nonhomologous end joining (cNHEJ), or by Polθ-mediated end joining (also known as alternative end joining (Alt-EJ) or microhomology mediate joining). Polθ is a multifunctional enzyme composed of a superfamily 2 Hel308-type helicase domain at the N terminus, a low-fidelity A-family polymerase domain at the C terminus, and a non-structured 25 central domain. The N-terminal helicase domain of polymerase theta is suggested to displace replication protein A and / or RAD51 molecules from 3′ single-stranded DNA to facilitate DNA synapsis at the microhomology sequences. Subsequently, Polθ-polymerase extends one end of the break by using the opposing strand of the other break end as a template. Polθ-polymerase can oscillate between templated and non-templated activities resulting in nucleotide insertions at alt-EJ repair 30 junctions. Polθ is also frequently overexpressed in human cancers and its overexpression is linked to poor prognosis in breast cancer. Furthermore, Polθ expression confers resistance to DSB-forming agents, including IR and chemotherapy drugs. Importantly, cancer cells that have defective HR or cNHEJ including BRCA1 or BRCA2 mutated breast and ovarian cancer cells become increasingly 35 dependent on Polθ for repair and survival. As a result, Polθ has emerged as a highly relevant cancer drug target. There is a need for new anti-cancer therapies and, in particular for Polθ inhibitor-based anti-cancer therapies. 1 PATENT ATTORNEY DOCKET: 51246-065WO2 Summary of the Invention The disclosure provides methods of measuring the pharmacodynamic activity of inhibitors of DNA replication associated proteins (e.g., human polymerase theta (Polθ) and poly(ADP-ribose) polymerase (PARP)) by measuring the focal accumulation of the cancerous inhibitor of protein 5 phosphatase 2A (CIP2A) protein. Further, the disclosure provides kits which may perform an assay for determining the pharmacodynamic activity of a Polθ inhibitor or a PARP inhibitor. In a first aspect the disclosure provides a method of evaluating the pharmacodynamic activity of an inhibitor selected from a Polθ inhibitor or a PARP inhibitor, including: (a) contacting an experimental cell with the inhibitor; (b) measuring an experimental CIP2A signal intensity in the 10 experimental cell; and (c) comparing the experimental CIP2A signal intensity to a reference CIP2A signal intensity. The experimental CIP2A signal intensity is proportional to proportional to the accumulation of CIP2A foci in the experimental cell. The pharmacodynamic activity of the inhibitor is proportional to the difference between the experimental CIP2A signal intensity and the reference CIP2A signal intensity. 15 In some embodiments, the experimental cell is obtained from an experimental tissue biopsy on a subject prior to step (a). In some embodiments, the tissue biopsy is a tumor biopsy and the experimental cell is a tumor cell. In a second aspect, the disclosure provides a method of measuring the efficacy of a treatment of a subject with an inhibitor selected from a Polθ inhibitor or a PARP inhibitor, the method including: 20 (a) obtaining an experimental tissue biopsy from the subject; (b) contacting an experimental cell from the experimental tissue biopsy the cell with the inhibitor; (c) measuring an experimental CIP2A signal intensity in the experimental cell; and (d) comparing the experimental CIP2A signal intensity with a reference CIP2A signal intensity. A treatment is determined to be more effective if the experimental CIP2A signal intensity is greater than the reference CIP2A signal intensity. 25 In some embodiments of the first or second aspect, the reference CIP2A signal intensity is measured in a reference cell. In some embodiments, the reference cell is obtained from a reference tissue biopsy. In some embodiments, the reference tissue biopsy is a tumor biopsy and the reference cell is a tumor cell. In some embodiments, the reference cell is a wild type cell. In some embodiments, the reference cell is obtained from the experimental tissue biopsy. In some embodiments, the 30 reference cell is not contacted with a Polθ inhibitor or a PARP inhibitor prior to measuring the reference signal intensity. In some embodiments, the reference CIP2A signal intensity is proportional to the CIP2A foci per mitotic event in the reference cell when the reference cell is contacted with a different inhibitor than the experimental cell. In some embodiments, the reference CIP2A signal intensity is proportional to the CIP2A foci per mitotic event obtained with a Polθ inhibitor or a PARP 35 inhibitor different from the experimental cell. In a third aspect, the disclosure provides A method of measuring the efficacy of a treatment of a subject with an inhibitor selected from a Polθ inhibitor or a PARP inhibitor, the method including: (a) obtaining a reference tissue biopsy from the subject, the reference tissue biopsy including a reference cell; (b) measuring a reference CIP2A signal intensity from the reference cell; (c) administering the 40 inhibitor to the subject; (d) allowing a duration of treatment to elapse; (e) obtaining an experimental 2 PATENT ATTORNEY DOCKET: 51246-065WO2 tissue biopsy from the subject, the experimental tissue biopsy including an experimental cell; (f) contacting the experimental cell with the inhibitor; (g) measuring an experimental CIP2A signal intensity in the experimental cell; and (h) comparing the experimental CIP2A signal intensity with a reference CIP2A signal intensity. A treatment is determined to be more effective if the experimental 5 CIP2A signal intensity is greater than the reference CIP2A signal intensity. In some embodiments, the duration of treatment is at least 1 day (e.g., at least 10 days, at least 20 days, at least 30 days, at least 45 days, or at least 60 days). In some embodiments, the inhibitor is administered continuously to the subject throughout the duration of treatment. In some embodiments, the inhibitor is administered on a dosing schedule to the subject throughout the 10 duration of treatment. In some embodiments, the reference tissue biopsy is a tumor biopsy and the reference cell is a tumor cell. In some embodiments, the reference cell is not contacted with a Polθ inhibitor or a PARP inhibitor prior to measuring the reference signal intensity. In some embodiments of any preceding aspect, the experimental tissue biopsy is a tumor biopsy and the experimental cell is a tumor cell. In some embodiments, the subject is suffering from a 15 disease or disorder. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a carcinoma, sarcoma, adenocarcinoma, leukemia, lymphoma, or melanoma. In some embodiments, the cancer is a carcinoma selected from the group consisting of medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma 20 of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct 25 carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, 30 infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous 35 carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell 40 carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell 3 PATENT ATTORNEY DOCKET: 51246-065WO2 carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum. In some embodiments, the cancer is a sarcoma selected from the group consisting of 5 chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy’s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented10 hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T- cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma. In some embodiments, the cancer is a leukemia selected from the group consisting of 15 nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell 20 leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic 25 leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia. In some embodiments, the cancer is a melanoma selected from the group consisting of acral- lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, 30 malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma. In some embodiments, the cancer is prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head & neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, 35 sarcoma, stomach cancer, uterus cancer, medulloblastoma, colorectal cancer, or pancreatic cancer. In some embodiments, the cancer is Hodgkin's disease, Non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, 40 lymphoma, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, 4 PATENT ATTORNEY DOCKET: 51246-065WO2 endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer. In some embodiments, the experimental cell is preserved before contacting the cell with the 5 inhibitor. In some embodiments, the experimental cell is preserved with formalin-fixed paraffin embedded (FFPE) tissue. In some embodiments, the reference cell is preserved before contacting the cell with the inhibitor. In some embodiments, the reference cell is preserved with FFPE tissue. In some embodiments, the experimental cell is not preserved before contacting the cell with the inhibitor. In some embodiments, the reference cell is not preserved before contacting the cell with the inhibitor. 10 In some embodiments, the experimental cell is homologous recombination (HR) proficient. In some embodiments, the reference cell is HR proficient. In some embodiments, the experimental cell is HR deficient. In some embodiments, the reference cell is HR deficient. In some embodiments, the reference CIP2A signal intensity is about 1% of mitotic events (e.g., about 5% of mitotic events) having a CIP2A foci number greater than a threshold value. In some 15 embodiments, the inhibitor or the treatment are identified as effective when the experimental CIP2A signal intensity is at least 1% of mitotic events (e.g., at least 5% of mitotic events, at least 10% of mitotic events, at least 15% of mitotic events, at least 20% of mitotic events, at least 30% of mitotic events, at least 40% of mitotic events, or at least 50% of mitotic events) having a CIP2A foci per mitotic event greater than a threshold value. In some embodiments, the threshold value is at least 5 20 CIP2A foci per mitotic event. In some embodiments, the threshold value is at least 10 CIP2A foci per mitotic event. In some embodiments, the measuring step includes immunostaining. In some embodiments, the measuring step includes an immunofluorescence step or immunohistochemistry step. In some embodiments, the measuring step includes staining with DNA topoisomerase 2-binding protein 1 25 (TOPBP1). In some embodiments, the measuring step includes staining with Mediator of DNA damage checkpoint 1 (MDC1). In some embodiments, the method includes contacting the cell with the Polθ inhibitor. In some embodiments, the Polθ inhibitor is a compound of formula (I): 30 or a pharmaceutically acceptable salt thereof, wherein V is N or CR; W is optionally substituted C1-6 alkylene, C1-6 alkoxyl, optionally substituted C2-6 alkenyl, 35 optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C1-6 alkylene, optionally substituted C1-6 heteroalkyl, optionally 5 PATENT ATTORNEY DOCKET: 51246-065WO2 substituted C2-6 alkenyl, optionally substituted allenyl, optionally substituted C2-6 alkynyl, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3- 8 cycloalkylene, RXis halo, amino, optionally substituted C1-6 alkoxyl, optionally substituted acyl, carboxyl, amido, optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally 5 substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; 10 Z is a H, halo, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, optionally substituted C2-6 alkenyl, acyl, or amido; and R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 15 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl. In some embodiments, V is N or CR; 20 W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L125 is -O-, -NRX1-, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3-8 cycloalkylene, RXis optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; 30 Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; and 35 R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl. In some embodiments, 40 V is N or CR; 6 PATENT ATTORNEY DOCKET: 51246-065WO2 W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or 5 optionally substituted C6-10 arylene; L1is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; 10 Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; and R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or 15 C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl. In some embodiments, V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally 20 substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally 25 substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; and R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 30 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl. In some embodiments, W is ethylene, ethynylene, or cyclopropylene. In some embodiments, V is N. In some embodiments, the Polθ inhibitor is a compound of formula (II): 35 or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ inhibitor is a compound of formula (III): 7 PATENT ATTORNEY DOCKET: 51246-065WO2 or a pharmaceutically acceptable salt thereof. In some embodiments, V is CR. In some embodiments, V is CH. 5 In some embodiments, the Polθ inhibitor is a compound of formula (IV): , or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ inhibitor is a compound of formula (V): 10 , or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ inhibitor is a compound of formula (VI): , 15 or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl or a C4-C9 heterocyclyl 20 optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH. 25 In some embodiments, the Polθ inhibitor is a compound of formula (VII): 8 PATENT ATTORNEY DOCKET: 51246-065WO2 , or a pharmaceutically acceptable salt thereof, wherein 5 n is 0 or 1; o is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl, C1-C6 perfluoroalkyl, halo, or a C4-C9 heterocyclyl optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; 10 RA3is hydrogen or a halogen; RA4is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-C9 cycloalkyl, optionally substituted C3-C9 heterocyclylene, halo, trifluoromethyl, CN, or optionally substituted C2-9 heteroarylene; or the bond between RA4and the cycloalkyl is an alkene. 15 each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH. In some embodiments, a prodrug of the Polθ inhibitor is contacted with the cell, or administered to the subject. In some embodiments, the Polθ inhibitor prodrug is of formula (PI) 20 (PI), or a pharmaceutically acceptable salt thereof wherein: 25 is an alkene of either E or Z isomeric configuration; V is N or CR; W is optionally substituted C1-6 alkylene, C1-6 alkoxyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl; 30 X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C1-6 alkylene, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted allenyl, optionally substituted C2-6 alkynyl, optionally 9 PATENT ATTORNEY DOCKET: 51246-065WO2 substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3- 8 cycloalkylene, RXis amino, halo, optionally substituted C1-6 alkoxyl, optionally substituted acyl, carboxyl, amido, optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 5 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, halo, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally 10 substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, optionally substituted C2-6 alkenyl, acyl, or amido; R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or 15 C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl; and M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, –RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is independently optionally substituted C1-6 alkyl, and each RM2is independently H, optionally substituted 20 C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl. In some embodiments, V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 25 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3-8 cycloalkylene, RXis optionally substituted C1-6 alkyl, optionally substituted 30 C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; 35 Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10; R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or 10 PATENT ATTORNEY DOCKET: 51246-065WO2 C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl; and M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, –RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is 5 independently optionally substituted C1-6 alkyl, and each RM2is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl. In some embodiments, V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally 10 substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene; L1is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally 15 substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, 20 optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl; and 25 M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, –RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is independently optionally substituted C1-6 alkyl, and each RM2is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl. In some embodiments, 30 V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or 35 optionally substituted C6-10 arylene; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 40 heteroaryl, or optionally substituted C6-10 aryl; and 11 PATENT ATTORNEY DOCKET: 51246-065WO2 R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl; and 5 M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, -RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is independently optionally substituted C1-6 alkyl, and each RM2is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl. In some embodiments, the Polθ inhibitor prodrug is a compound of formula (PIIb): 10 or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ inhibitor prodrug is a compound of formula (PIIIb): 15 or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ inhibitor prodrug is a compound of formula (PIVb): , 20 or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ inhibitor prodrug is a compound of formula (PVb): , or a pharmaceutically acceptable salt thereof. 25 In some embodiments, the Polθ inhibitor prodrug is a compound of formula (PVIb): 12 PATENT ATTORNEY DOCKET: 51246-065WO2 , or a pharmaceutically acceptable salt thereof, wherein 5 n is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl or a C4-C9 heterocyclyl optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; 10 each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH. In some embodiments, the Polθ inhibitor prodrug is a compound of formula (PVIIb): , 15 or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; o is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl, C1-C6 perfluoroalkyl, halo, or 20 a C4-C9 heterocyclyl optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; 13 PATENT ATTORNEY DOCKET: 51246-065WO2 RA4is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-C9 cycloalkyl, optionally substituted C3-C9 heterocyclylene, halo, trifluoromethyl, CN, or optionally substituted C2-9 heteroarylene; or the bond between RA4and the cycloalkyl is an alkene; 5 each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH. In some embodiments, the Polθ inhibitor, or a prodrug of the Polθ inhibitor is a compound selected from Table 1. In some embodiments, the Polθ inhibitor, or a prodrug of the Polθ inhibitor is a compound selected from Table 2. 10 In some embodiments, the method includes contacting the cell with the PARP inhibitor. In some embodiments, the PARP inhibitor is selected from the group consisting of talazoparib, niraparib, rucaparib, olaparib, AZD5305, veliparib, iniparib, 2X-121, CEP-9722, AZD9574, pamiparib, DSB1559, EIK1003, HRS-1167, HS-10502, LAE119, SNV1521 and pharmaceutically acceptable salts or isotopically enriched variants thereof. 15 In some embodiments, the PARP inhibitor is a compound of formula (III): , wherein X1and X2are each independently selected from N and C(H), 20 X3is independently selected from N and C(R4), wherein R4is H or fluoro, R1is C1-4alkyl or C1-4fluoroalkyl, R2is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl, and R3is H or C1-4 alkyl, or a pharmaceutically acceptable salt thereof 25 provided that: when X1is N, then X2is C(H), and X3is C(R4), when X2is N, then X1═C(H), and X3is C(R4), and when X3is N, then X1and X2are both C(H) or formula (IV), 30 14 PATENT ATTORNEY DOCKET: 51246-065WO2 wherein R1 is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C1-4 fluoroalkyl, and C1-4 alkyloxy; R2 is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl; 5 R3 is H or C1-4 alkyl; and R4 is halo or C1-4 alkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is: 5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- 10 carboxamide, 5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2-carboxamide, 6-chloro-5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, 15 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2-carboxamide, 6-chloro-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl- 20 pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 6-ethyl-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-6- 25 (trifluoromethyl)pyridine-2-carboxamide, 6-(difluoromethyl)-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 30 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- 35 carboxamide, N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2- carboxamide, 6-chloro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1- yl]pyridine-2-carboxamide, 15 PATENT ATTORNEY DOCKET: 51246-065WO2 6-fluoro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1- yl]pyridine-2-carboxamide, N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, 5 6-chloro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, 6-fluoro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- 10 pyridine-2-carboxamide, 5-[4-[[2-(1,1-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine- 2-carboxamide, 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine- 2-carboxamide, 15 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2-carboxamide, 5-[4-[[2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-fluoro-5-[4-[[2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl- 20 pyridine-2-carboxamide, N-methyl-5-[4-[[3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine- 2-carboxamide, 6-fluoro-N-methyl-5-(4-((3-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-6-yl)methyl) piperazin-1-yl)picolinamide, 25 or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is: 6-(difluoromethyl)-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N- 30 methyl-pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-6 (trifluoromethyl)pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 35 N-ethyl-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide or a pharmaceutically acceptable salt 40 thereof. 16 PATENT ATTORNEY DOCKET: 51246-065WO2 In some embodiments, the PARP inhibitor is: 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine- 2- carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- 5 carboxamide, 6-chloro-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 10 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridine-2- carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2- carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2- 15 carboxamide, 6-chloro-5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2- carboxamide, 20 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine- 2- carboxamide, 6-fluoro-5-[4-[[5-fluoro-2-[(1 S and 1 R)-1 -fluoroethyl]-3-oxo-4H-quinoxalin-6- 25 yl]methyl]piperazin-1 -yl]-N- methyl-pyridine-2-carboxamide, 5-[4-[[5-fluoro-2-[(1 S and 1 R)-1 -fluoroethyl]-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]- N,6- dimethyl-pyridine-2-carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 30 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2- carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2- carboxamide, 5-[4-[[2-(1 ,1-difluoroethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N, 6- 35 dimethyl- pyridine-2-carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 6-(difluoromethyl)-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- 40 carboxamide, 17 PATENT ATTORNEY DOCKET: 51246-065WO2 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 6-(difluoromethyl)-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl- pyridine-2-carboxamide, 5 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2- carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2- carboxamide, 10 6-chloro-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- 15 pyridine-2- carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine- 2- carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 20 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- 25 carboxamide, 6-fluoro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[[2-(difluoromethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N, 6- dimethyl- pyridine-2-carboxamide, 30 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine- 2-carboxamide, 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- 35 pyridine-2- carboxamide, 6-chloro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine- 2-carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine- 2- carboxamide, 18 PATENT ATTORNEY DOCKET: 51246-065WO2 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2- carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5 N-ethyl-6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]pyridine-2- carboxamide, N-ethyl-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl- pyridine-2- carboxamide, 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N, 6- 10 dimethyl- pyridine-2-carboxamide, 6-fluoro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N- methyl- pyridine-2-carboxamide, 6-chloro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N- methyl- pyridine-2-carboxamide, 15 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine- 2-carboxamide, 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- 20 pyridine-2- carboxamide, 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine- 2- carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N- methyl- pyridine-2-carboxamide, 25 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2- carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- 30 pyridine-2- carboxamide, 6-fluoro-5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine- 2-carboxamide, 6-(difluoromethyl)-5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]- N- methyl-pyridine-2-carboxamide, 35 6-(difluoromethyl)-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl- pyridine-2-carboxamide, or a pharmaceutically acceptable salts thereof. In some embodiments, the PARP inhibitor is 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, or a pharmaceutically 40 acceptable salt thereof. 19 PATENT ATTORNEY DOCKET: 51246-065WO2 In some embodiments, the PARP inhibitor is 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide. In some embodiments, the PARP inhibitor is a compound selected from Table 3. In some embodiments, the method includes contacting the cell with the PARP inhibitor and the Polθ inhibitor 5 simultaneously. In some embodiments, the method includes contacting the cell with the PARP inhibitor and the Polθ inhibitor sequentially. In a fourth aspect, the disclosure provides a kit for performing the method of any preceding aspect, including an assay buffer and a means for visualizing CIP2A. In some embodiments, the kit further includes (a) a Polθ inhibitor or a PARP inhibitor; (b) an assay buffer; (c) a multi-well plate; and 10 (d) a stain. In a fifth aspect, the disclosure provides a kit (e.g., for performing an assay to determine the susceptibility of a subject for treatment with a Polθ inhibitor or a PARP inhibitor), including: (a) a Polθ inhibitor or a PARP inhibitor; (b) an assay buffer; (c) a multi-well plate; and (d) a stain including an antigen specific to CIP2A chemically bound or conjugated to a dye amenable to visualization with a 15 visualization means. In some embodiments of the fourth or fifth aspect, the kit includes the Polθ inhibitor, and the Polθ inhibitor is selected from Table 1. In some embodiments, the kit includes the Polθ inhibitor, and the Polθ inhibitor is selected from Table 2. In some embodiments, the kit includes the PARP inhibitor, and the PARP inhibitor is selected from Table 3. In some embodiments, the assay further includes a 20 cell obtained from a subject. In some embodiments, the cell is a cancer cell. In some embodiments of the fourth aspect, the kit includes: (a) a cell; (b) an assay buffer; (c) a multi-well plate; and (d) a stain including an antigen specific to CIP2A chemically bound or conjugated to a dye amenable to visualization with a visualization means. In a sixth aspect, the disclosure provides a kit (e.g., for performing an assay to determine the 25 pharmacodynamic activity of a Polθ inhibitor or a PARP inhibitor), including: (a) a cell; (b) an assay buffer; (c) a multi-well plate; and (d) a stain including an antigen specific to CIP2A chemically bound or conjugated to a dye amenable to visualization with a visualization means. In some embodiments of the fourth or sixth aspect, the cell is a preserved cell. In some embodiments, the cell is preserved with FFPE tissue. In some embodiments, the cell is a live cell. In 30 some embodiments, the assay includes contacting the cell with a Polθ inhibitor or a PARP inhibitor. In some embodiments, the assay includes contacting the cell with the Polθ inhibitor, wherein the Polθ inhibitor is selected from Table 1. In some embodiments, the assay includes contacting the cell with the Polθ inhibitor, wherein the Polθ inhibitor is selected from Table 2. In some embodiments, the assay includes contacting the cell with includes the PARP inhibitor, wherein the PARP inhibitor is 35 selected from Table 3. In some embodiments, the stain includes TOPBP1. In some embodiments, the stain includes MDC1. In some embodiments, the visualization means includes fluorescence microscopy, confocal fluorescence microscopy, or bright field microscopy. In some embodiments, the method further includes administering an additional anticancer 40 therapy. In some embodiments, the additional anticancer therapy is a radiotherapy, a radioligand, an 20 PATENT ATTORNEY DOCKET: 51246-065WO2 ADC, an immune checkpoint inhibitor, a DNA-PK inhibitor, an ATM inhibitor, an ATR inhibitor, a Wee1 inhibitor, a PKMYT1 inhibitor, or a CHK1 inhibitor. In some embodiments, the radioligand is selected from the group consisting of zevalin, actimab-A, iomab-ACT, iomab-B, lutetium-177-DOTAGA-PEG-IAC, tozaride, SS0110, BAY-2701439, 5177Lu-rhPSMA-10.1, CTT-1403, iopofosine, SAR-BBN, SAR-bisPSMA, SARTATE, FAP-2286, CONV- 01-α,177Lu-PSMA-I&T, FPI-2059, FPI-1434, FPI-1966, [177Lu] ludotadipep,161Tb-PSMA-I&T, ITM-31, ITM-11, JNJ-69086420, I-131-1095, azedra, PSMA TTC / BAY-2315497,177Lu-DOTA-EB-TATE, betalutin, AAA817, AAA603, lutathera, pluvicto, PPMX-T002, 186RNL, PNT2003, CAM-H2, AlphaMedix, RYZ101, Sn-117m-DTPA, TLX592, TLX66, TLX250, TLX591, TLX101,124I-omburtamab, 10 GD2-SADA,131I-omburtamab, and pharmaceutically acceptable salts thereof. In some embodiments, the ADC is selected from the group consisting of disitamab vedotin, belantamab mafodotin, trastuzumab deruxtecan, ujvira, mirvetuximab soravtansine, gemtuzumab ozogamicin, enfortumab vedotin, inotuzumab ozogamicin, trastuzumab emtansine, tisotumab vedotin, sacituzumab govitecan, polatuzumab vedotin, loncastuximab tesirine, brentuximab vedotin, PF-15 06804103, MGTA-117, FOR46, MRG001, SOT102, ZV0203, AOC 1020, PRO1184, BAT8009, BB- 1705, JS107, SHR-A1912, CMG901, ladiratuzumab vedotin, BAT8006, RC108, BAT8008, mipasetamab uzoptirine, NBE-002, zanidatamab zovodotin, F0002-ADC, SKB315, GQ1001, ABBV- 637, XMT-2056, TORL-1-23, FDA022, DYNE-251, STI-6129, ozuriftamab vedotin, farletuzumab ecteribulin, trastuzumab vedotin, DB-1303, OMTX705, TRS005, ispectamab debotansine, DXC-005, 20 ESG-401, ARX788, BAT8010, tusamitamab ravtansine, ABBV-154, naratuximab emtansine, PSMA ADC, TAK-164, ADCT-602, ADCT-901, SHR-A1201, GB251, ABL202, SHR-A1921, 9MW2821, HS- 20093, BIO-106, SKB264, camidanlumab tesirine, datopotamab deruxtecan, telisotuzumab vedotin, L-DOS47, AVID100, OBI-999, DP303c, AURIXIM, MT-8633, IMGC936, BB-1701, AOC 1001, JS108, TAC-001, SYSA1801, SHR-A2009, TORL-2-307-ADC, BL-M07D1, STRO-001, A166, mecbotamab 25 vedotin, trastuzumab duocarmazine, ASN004, ABBV-011, mirzotamab clezutoclax, OBT076, HS630, SGN-STNV, FDA018, ABBV-400, AZD8205, IBI-343, SGN-ALPV, TAK-500, JBH492, ALT-P7, ifinatamab deruxtecan, DXC-004, IMGN151, XMT-1660, M1231, LM-102, ORM-5029, STI-3258, SGN-B7H4V, TPX-4589, IKS03, zilovertamab vedotin, ARX517, pivekimab sunirine, lonigutamab ugodotin, TRPH-222, MRG004a, DS-6000a, REGN5093-M114, trastuzumab imbotolimod, RC88, 30 HTI-1066, BI-CON-02, SGN-CD228A, AOC 1044, DB-1305, ABBV-319, patritumab deruxtecan, RC118, trastuzumab rezetecan, ARX305, upifitamab rilsodotin, NBT828, TAA013, BL-B01D1, BL- M02D1, GQ1007, DS-9606a, NBT508, B003, DX126-262, XB002, FS-1502, praluzatamab ravtansine, AMT-151, M9140, indatuximab ravtansine, cofetuzumab pelidotin, RG7861, AGS62P1, CX-2029, SGN-B6A, RC98 ADC, DYNE-101, SHR-A1904, anetumab ravtansine, vobramitamab duocarmazine,35 luveltamab tazevibulin, serclutamab talirine, MRG003, SYD1875, BYON3521, SGN-PDL1V, JSKN- 003, YL201, HS-20089, DXC-007, SYS6002, and HDP-101. In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of anti CTLA-4 ipilimumab, anti PD-1 nivolumab, anti PD-1 pembrolizumab, anti PD-1 cemiplimab, anti PD-L1 atezolizumab, anti PD-L1 avelumab, and anti PD-L1 durvalumab. 21 PATENT ATTORNEY DOCKET: 51246-065WO2 In some embodiments, the DNA-PK inhibitor is selected from the group consisting of AZD- 7648, peposertib, M9831, IMP11, NU5455, BAY-8400, ZL-2201, XRD-0394, avadomide, CC-115, KU57788, ZSTK474, LY3023414, BR101801, XRD-0394, NK-314, and pharmaceutically acceptable salts thereof. 5 Abbreviations Abbreviations and terms that are commonly used in the fields of organic chemistry, medicinal chemistry, pharmacology, and medicine and are well known to practitioners in these fields are used herein. Representative abbreviations and definitions are provided below: 10 Ac is acetyl [CH3C(O)-], Ac2O is acetic anhydride; AcOH is acetic acid; APC is antigen- presenting cell; aq. is aqueous; 9-BBN is 9-borabicyclo[3.3.1]nonane; BINAP is (2,2′- bis(diphenylphosphino)-1,1′-binaphthyl); Bn is benzyl; Boc is tert-butyloxycarbonyl; CDI is carbonyldiimidazole; DCM is dichloromethane; DIAD is diisopropylazodicarboxylate; DIBAL is diisobutylaluminum hydride; DIPEA is diisoproplyethyl amine; DMA is dimethylacetamide; DMAP is 4-15 dimethylaminopyridine; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; dppf is 1,1'- bis(diphenylphosphino)ferrocene; EDAC (or EDC) is 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide HCl; ESI is electrospray ionization mass spectrometry; Et2O is diethyl ether; Et3N is triethylamine; Et is ethyl; EtOAc is Ethyl acetate; EtOH is ethanol; 3-F-Ph is 3-fluorophenyl, HATU is (1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCl is 20 hydrochloric acid; HOBt is 1-hydroxybenzotriazole; HPLC is high performance liquid chromatography; IPA is isopropyl alcohol; LCMS is HPLC with mass spectral detection; LiHMDS is lithium bis(trimethylsilyl)amide; LG is leaving group; M is molar; mCPBA is metachloroperbenzoic acid; MC is methylcellulose; mmol is millimole; Me is methyl; MeCN is acetonitrile; MeOH is methanol; Ms is methanesulfonyl; MS is mass spectrometry; MW is microwave; N is normal; NaHMDS is sodium25 hexamethyldisiliazide; NaOAc is sodium acetate; NaOtBu is sodium tert-butoxide; NMO is N- methylmorpholine N-oxide; NMP is N-methyl pyrrolidinone; NMR is nuclear magnetic resonance spectroscopy; Pd(PPh3)4 is Palladium-tetrakis(triphenylphosphine); PdCl2(dtbpf) is [1,1′-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II); Pd(t-Bu3P)2 is Bis(tri-tert-butylphosphine)palladium(0); Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium; PdCl2(PPh3)2 is dichlorobis- 30 (triphenylphosphene)palladium; PG Denotes an unspecified protecting group; Ph is phenyl; PhMe is toluene; PPh3 is triphenylphosphine; PMB is para-methoxybenzyl; rt is room temperature; RBF is round-bottom flask; RuPhos Pd G1 is chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′- biphenyl)[2-(2-aminoethyl)phenyl]palladium(II); SEM is [2-(trimethylsilyl)ethoxy]methyl; SFC is supercritical fluid chromatography; SLS is sodium lauryl sulfate; SNAr is nucleophilic aromatic35 substitution; S-Phos Pd G3 is (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) [2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate: P(tBu)3 Pd G4 is 2-[2-[tert-butyl(phenyl)phosphanyl]phenyl]- 1-N,1-N,3-N,3-N-tetramethylbenzene-1,3-diamine;methanesulfonic acid;N-methyl-2- phenylaniline;palladium; T3P is propanephosphonic acid anhydride; TBAB is tetrabutyl ammonium bromide; TBAF is tetrabutyl ammonium fluoride; TBS is tert-butyldimethylsilyl; tBu is tert-butyl; Tf is 22 PATENT ATTORNEY DOCKET: 51246-065WO2 triflate; TFA is trifluoroacetic acid; THF is tetrahydrofuran; THP is tetrahydropyran; TLC is thin layer chromatography; TMAD is tetramethylazodicarboxamide; TMS is trimethylsilyl; TPAP is tetrapropylammonium perruthenate; TPGS is tocopherol polyethylene glycol succinate; Ts is p- toluenesulfonyl; UPLC is ultra performance liquid chromatography; Xantphos is (9,9-dimethyl-9H- 5 xanthene-4,5-diyl)bis(diphenylphosphane); Xantphos Pd G3 is [(4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate. Definitions The terms “aberration” and “aberrant,” as used herein, refer to different from normal. When 10 used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, where returning the aberrant activity to a normal or non- disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms. The aberrant activity 15 can be measured by measuring the modification of a substrate of the enzyme in question; a difference of greater or equal to a 2-fold change in activity could be considered as aberrant. Aberrant activity could also refer to an increased dependence on a particular signaling pathway as a result of a deficiency in a separate complementary pathway. The term “acyl,” as used herein, represents a group –C(=O)–R, where R is alkyl, alkenyl, 20 alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl. Acyl may be optionally substituted as described herein for each respective R group. The term “adenocarcinoma,” as used herein, represents a malignancy of the arising from the glandular cells that line organs within an organism. Non-limiting examples of adenocarcinomas include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and 25 colorectal cancer. The term “alkanoyl,” as used herein, represents a hydrogen or an alkyl group that is attached to the parent molecular group through a carbonyl group and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, propionyl, butyryl, and iso-butyryl. Unsubstituted alkanoyl groups contain from 1 to 7 carbons. The alkanoyl group may be unsubstituted of substituted (e.g., optionally 30 substituted C1-7 alkanoyl) as described herein for alkyl group. The ending “-oyl” may be added to another group defined herein, e.g., aryl, cycloalkyl, and heterocyclyl, to define “aryloyl,” “cycloalkanoyl,” and “(heterocyclyl)oyl.” These groups represent a carbonyl group substituted by aryl, cycloalkyl, or heterocyclyl, respectively. Each of “aryloyl,” “cycloalkanoyl,” and “(heterocyclyl)oyl” may be optionally substituted as defined for “aryl,” “cycloalkyl,” or “heterocyclyl,” respectively. 35 The term “alkenyl,” as used herein, represents acyclic monovalent straight or branched chain hydrocarbon groups of containing one, two, or three carbon-carbon double bonds. Non-limiting examples of the alkenyl groups include ethenyl, prop-1-enyl, prop-2-enyl, 1-methylethenyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylprop-1-enyl, 2-methylprop-1-enyl, and 1-methylprop-2-enyl. Alkenyl groups may be optionally substituted as defined herein for alkyl. 23 PATENT ATTORNEY DOCKET: 51246-065WO2 The term “alkenylene,” as used herein, refers to a divalent alkenyl group. An optionally substituted alkenylene is an alkenylene that is optionally substituted as described herein for alkyl. The term “alkoxy,” as used herein, represents a chemical substituent of formula –OR, where R is a C1-6 alkyl group, unless otherwise specified. In some embodiments, the alkyl group can be 5 further substituted as defined herein. The term “alkoxy” can be combined with other terms defined herein, e.g., aryl, cycloalkyl, or heterocyclyl, to define an “aryl alkoxy,” “cycloalkyl alkoxy,” and “(heterocyclyl)alkoxy” groups. These groups represent an alkoxy that is substituted by aryl, cycloalkyl, or heterocyclyl, respectively. Each of “aryl alkoxy,” “cycloalkyl alkoxy,” and “(heterocyclyl)alkoxy” may optionally substituted as defined herein for each individual portion. 10 The term “alkoxyalkyl,” as used herein, represents a chemical substituent of formula –L–O–R, where L is C1-6 alkylene, and R is C1-6 alkyl. An optionally substituted alkoxyalkyl is an alkoxyalkyl that is optionally substituted as described herein for alkyl. The term “alkoxycarbonylamino,” as used herein, represents a chemical substituent of formula -N(R1)COOR2, where R1is H or optionally substituted alkyl, and R2is optionally substituted 15 alkyl. The term “alkyl,” as used herein, refers to an acyclic straight or branched chain saturated hydrocarbon group, which, when unsubstituted, has from 1 to 12 carbons, unless otherwise specified. In certain preferred embodiments, unsubstituted alkyl has from 1 to 6 carbons. Alkyl groups are exemplified by methyl; ethyl; n- and iso-propyl; n-, sec-, iso- and tert-butyl; neopentyl, and the like, 20 and may be optionally substituted, valency permitting, with one, two, three, or, in the case of alkyl groups of two carbons or more, four or more substituents independently selected from the group consisting of: amino; alkoxy; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; alkylsulfonyl; alkylsulfinyl; alkylsulfenyl; =O; =S; -SO2R, where R is amino or cycloalkyl; =NR’, where R’ is H, alkyl, 25 aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or, valency permitting, substituted with unsubstituted substituent(s) defined herein for each respective group. The term “alkylene,” as used herein, refers to a divalent alkyl group. An optionally substituted alkylene is an alkylene that is optionally substituted as described herein for alkyl. The term “alkylamino,” as used herein, refers to a group having the formula –N(RN1)2 or – 30 NHRN1, in which RN1is alkyl, as defined herein. The alkyl portion of alkylamino can be optionally substituted as defined for alkyl. Each optional substituent on the substituted alkylamino may itself be unsubstituted or, valency permitting, substituted with unsubstituted substituent(s) defined herein for each respective group. The term “alkylphosphonyl,” as used herein, represents a group of formula -(alkyl)-O- 35 P(O)(ORP)(ORP), wherein each RPis independently absent, H, or alkyl. When RPis absent, the alkylphosphonyl is an anion of formula -(alkyl)-O-P(O)(O–)(ORP) or -(alkyl)-O-P(O)(O–)2. The anionic alkylphosphonyl group may be associated with a cation (e.g., a pharmaceutically acceptable cation, e.g., an alkali metal cation (e.g., a sodium, lithium, or potassium, ion), an alkaline earth metal cation (e.g., a calcium or magnesium ion), nontoxic ammonium cations (e.g., tetramethylammonium or 40 tetraethylammonium cations), and nontoxic amine cations (e.g., methylamine, dimethylamine, 24 PATENT ATTORNEY DOCKET: 51246-065WO2 trimethylamine, ethylamine, and triethylamine cations). In some embodiments, the cation is a sodium cation. Alkylphosphonyl may be optionally substituted as defined for alkyl. The term “alkylacylphosphonyl,” as used herein, represents a group of formula -(alkyl)-(acyl)- O-P(O)(ORP)(ORP), wherein each RPis as defined for alkylphosphonyl. The R group of the acyl group 5 may be any R group as defined for acyl. In some embodiments, alkylacylphosphonyl may be a group of formula - (alkyl)-CO-(alkyl)-P(O)(ORP)(ORP). Alkylacylphosphonyl may be optionally substituted as defined for alkyl. The term “alkylsulfenyl,” as used herein, represents a group of formula –S–(alkyl). Alkylsulfenyl may be optionally substituted as defined for alkyl. 10 The term “alkylsulfinyl,” as used herein, represents a group of formula –S(O)–(alkyl). Alkylsulfinyl may be optionally substituted as defined for alkyl. The term “alkylsulfonyl,” as used herein, represents a group of formula –S(O)2–(alkyl). Alkylsulfonyl may be optionally substituted as defined for alkyl. The term “alkynyl,” as used herein, represents monovalent straight or branched chain 15 hydrocarbon groups of from two to six carbon atoms containing at least one carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like. The alkynyl groups may be unsubstituted or substituted (e.g., optionally substituted alkynyl) as defined for alkyl. The term “allenyl,” as used herein, refers to univalent hydrocarbons having two double bonds from one carbon atom to two others, e.g., -R1-C=C=C-R2-, where R1and R2are independently H, 20 optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl. The term “alkynylene,” as used herein, refers to a divalent alkynyl group. An optionally substituted alkynylene is an alkynylene that is optionally substituted as described herein for alkyl. The term “amino,” as used herein, represents –N(RN1)2, where, if amino is unsubstituted, both25 RN1are H; or, if amino is substituted, each RN1is independently H, -OH, -NO2, -N(RN2)2, -SO2ORN2, - SO2RN2, -SORN2, -COORN2, an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, cycloalkyl, cycloalkenyl, heteroalkyl, or heterocyclyl, provided that at least one RN1is not H, and where each RN2is independently H, alkyl, or aryl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective 30 group. In some embodiments, amino is unsubstituted amino (i.e., -NH2) or substituted amino (e.g., NHRN1), where RN1is independently -OH, SO2ORN2, -SO2RN2, -SORN2, -COORN2, optionally substituted alkyl, or optionally substituted aryl, and each RN2can be optionally substituted alkyl or optionally substituted aryl. In some embodiments, substituted amino may be alkylamino, in which the alkyl groups are optionally substituted as described herein for alkyl. In some embodiments, an amino 35 group is –NHRN1, in which RN1is optionally substituted alkyl. The term “aryl,” as used herein, represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings. Aryl group may include from 6 to 10 carbon atoms. All atoms within an unsubstituted carbocyclic aryl group are carbon atoms. Non-limiting examples of carbocyclic aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 40 fluorenyl, indanyl, and indenyl. The aryl group may be unsubstituted or substituted with one, two, 25 PATENT ATTORNEY DOCKET: 51246-065WO2 three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkyl alkyl; cycloalkyl alkynyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; heterocyclyl alkyl; heterocyclyl alkynyl; hydroxy; nitro; thiol; silyl; and 5 cyano. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group. The term “aryl alkyl,” as used herein, represents an alkyl group substituted with an aryl group. The aryl and alkyl portions may be optionally substituted as the individual groups as described herein. The term “arylene,” as used herein, refers to a divalent aryl group. An optionally substituted 10 arylene is an arylene that is optionally substituted as described herein for aryl. The term “aryloxy,” as used herein, represents a chemical substituent of formula –OR, where R is an aryl group, unless otherwise specified. In optionally substituted aryloxy, the aryl group is optionally substituted as described herein for aryl. The term “cancer,” as used herein, refers to all types of cancer, neoplasm or malignant 15 tumors found in mammals (e.g., humans), including leukemia, carcinomas and sarcomas. Non-limiting examples of cancers that may be treated with a compound or method provided herein include cancer of the prostate, thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, colorectal cancer, and pancreatic cancer. Additional non-limiting examples may 20 include, Hodgkin's disease, Non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, 25 endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, and prostate cancer. The term “carbocyclic,” as used herein, represents an optionally substituted C3-16 monocyclic, bicyclic, or tricyclic structure in which the rings, which may be aromatic or non-aromatic, 30 are formed by carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloalkynyl, and certain aryl groups. The term “carbonyl,” as used herein, represents a –C(O)– group. The term “carcinoma,” as used herein, refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Non-limiting examples of 35 carcinomas that may be treated with a compound or method provided herein include, e.g., medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar 40 carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic 26 PATENT ATTORNEY DOCKET: 51246-065WO2 carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni 5 carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma 10 lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell 15 carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, 20 carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum. The term “cyano,” as used herein, represents –CN group. The term “cycloalkenyl,” as used herein, refers to a non-aromatic carbocyclic group having at least one double bond in the ring and from three to ten carbons (e.g., a C3-10 cycloalkenyl), unless otherwise specified. Non-limiting examples of cycloalkenyl include cycloprop-1-enyl, cycloprop-2-enyl, 25 cyclobut-1-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, norbornen-1-yl, norbornen-2-yl, norbornen-5-yl, and norbornen-7-yl. The cycloalkenyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkenyl) as described for cycloalkyl. The term “cycloalkenyl alkyl,” as used herein, represents an alkyl group substituted with a cycloalkenyl group, each as defined herein. The cycloalkenyl and alkyl portions may be substituted as 30 the individual groups defined herein. The term “cycloalkoxy,” as used herein, represents a chemical substituent of formula –OR, where R is cycloalkyl group, unless otherwise specified. In some embodiments, the cycloalkyl group can be further substituted as defined herein. The term “cycloalkyl,” as used herein, refers to a cyclic alkyl group having from three to ten 35 carbons (e.g., a C3-C10 cycloalkyl), unless otherwise specified. Cycloalkyl groups may be monocyclic or bicyclic. Bicyclic cycloalkyl groups may be of bicyclo[p.q.0]alkyl type, in which each of p and q is, independently, 1, 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 2, 3, 4, 5, 6, 7, or 8. Alternatively, bicyclic cycloalkyl groups may include bridged cycloalkyl structures, e.g., bicyclo[p.q.r]alkyl, in which r is 1, 2, or 3, each of p and q is, independently, 1, 2, 3, 4, 5, or 6, provided 40 that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8. The cycloalkyl group may be a spirocyclic group, e.g., 27 PATENT ATTORNEY DOCKET: 51246-065WO2 spiro[p.q]alkyl, in which each of p and q is, independently, 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 4, 5, 6, 7, 8, or 9. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[2.2.1.]heptyl, 2-bicyclo[2.2.1.]heptyl, 5- bicyclo[2.2.1.]heptyl, 7-bicyclo[2.2.1.]heptyl, and decalinyl. The cycloalkyl group may be unsubstituted 5 or substituted (e.g., optionally substituted cycloalkyl) with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; =O; =S; -SO2R, where R is amino or cycloalkyl; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl; 10 or –CON(RA)2, where each RAis independently H or alkyl, or both RA, together with the atom to which they are attached, combine to form heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group. The term “cycloalkyl alkyl,” as used herein, represents an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl portions may be optionally 15 substituted as the individual groups described herein. The term “cycloalkyl alkynyl,” as used herein, represents an alkynyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkynyl portions may be optionally substituted as the individual groups described herein. The term “cycloalkylamino,” as used herein, represents a group -NHR, where R is cycloalkyl, 20 as defined herein. An optionally substituted cycloalkylamino is a cycloalkylamino that is optionally substituted as described herein for cycloalkyl. The term “cycloalkylene,” as used herein, represents a divalent cycloalkyl group. An optionally substituted cycloalkylene is a cycloalkylene that is optionally substituted as described herein for cycloalkyl. 25 The term “cycloalkynyl,” as used herein, refers to a monovalent carbocyclic group having one or two carbon-carbon triple bonds and having from eight to twelve carbons, unless otherwise specified. Cycloalkynyl may include one transannular bond or bridge. Non-limiting examples of cycloalkynyl include cyclooctynyl, cyclononynyl, cyclodecynyl, and cyclodecadiynyl. The cycloalkynyl group may be unsubstituted or substituted (e.g., optionally substituted cycloalkynyl) as defined for 30 cycloalkyl. The term “dicycloalkylamino,” as used herein, represents a group -NR2, where each R is independently cycloalkyl, as defined herein. An optionally substituted dicycloalkylamino is a dicycloalkylamino that is optionally substituted as described herein for cycloalkyl. The terms “disease” or “condition,” as used herein, refer to a state of being or health status of 35 a patient or subject capable of being treated with the compounds or methods provided herein. The terms “focus” and “foci,” as used herein, refers to an accumulation of DNA repair proteins formed in the vicinity of DNA damage. As a result of the accumulation of protein at a focus, the foci may be visualized using an appropriate means for visualizing molecular locations within a cell. Exemplary methods include immunofluorescence, formation of fluorescent protein fusion constructs, 40 and immunohistochemical staining methods A focus may include, e.g., at least one unique protein 28 PATENT ATTORNEY DOCKET: 51246-065WO2 (e.g., at least 2 unique proteins or at least 3 unique proteins) per focus. In some embodiments, the unique proteins include cancerous inhibitor of protein phosphatase 2A (CIP2A), topoisomerase 2- binding protein 1 (TOPBP1), or mediator of DNA damage checkpoint 1 (MDC1). In some embodiments, the methods of the present disclosure include determining the formation of CIP2A foci 5 in a cell in response to contacting the cell with a DNA damage response protein inhibitor. In some embodiments, the percentage of mitotic events with at least 10 CIP2A foci is determined. In some embodiments, the percentage of mitotic events with at least 5 CIP2A foci is determined. In some embodiments, the number of CIP2A foci in the nucleus is determined. The term “halo,” as used herein, represents a halogen selected from bromine, chlorine, 10 iodine, and fluorine. The term “heteroalkyl,” as used herein refers to an alkyl, alkenyl, or alkynyl group interrupted once by one or two heteroatoms; twice, each time, independently, by one or two heteroatoms; three times, each time, independently, by one or two heteroatoms; or four times, each time, independently, by one or two heteroatoms. Each heteroatom is, independently, O, N, or S. In some embodiments, 15 the heteroatom is O or N. None of the heteroalkyl groups includes two contiguous oxygen or sulfur atoms. The heteroalkyl group may be unsubstituted or substituted (e.g., optionally substituted heteroalkyl). When heteroalkyl is substituted and the substituent is bonded to the heteroatom, the substituent is selected according to the nature and valency of the heteroatom. Thus, the substituent bonded to the heteroatom, valency permitting, is selected from the group consisting of =O, -N(RN2)2, - 20 SO2ORN3, -SO2RN2, -SORN3, -COORN3, an N protecting group, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, or cyano, where each RN2is independently H, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl, and each RN3is independently alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl. Each of these substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective 25 group. When heteroalkyl is substituted and the substituent is bonded to carbon, the substituent is selected from those described for alkyl, provided that the substituent on the carbon atom bonded to the heteroatom is not Cl, Br, or I. It is understood that carbon atoms are found at the termini of a heteroalkyl group. The term “heteroaryl alkyl,” as used herein, represents an alkyl group substituted with a 30 heteroaryl group, each as defined herein. The heteroaryl and alkyl portions may be optionally substituted as the individual groups described herein. The term “heteroarylene,” as used herein, represents a divalent heteroaryl. An optionally substituted heteroarylene is a heteroarylene that is optionally substituted as described herein for heteroaryl. 35 The term “heteroaryloxy,” as used herein, refers to a structure –OR, in which R is heteroaryl. Heteroaryloxy can be optionally substituted as defined for heterocyclyl. The term “heterocyclyl,” as used herein, represents a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused, bridging, and / or spiro 3-, 4-, 5-, 6-, 7-, or 8-membered rings, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected 40 from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, “heterocyclyl” is a 29 PATENT ATTORNEY DOCKET: 51246-065WO2 monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused or bridging 5-, 6-, 7-, or 8- membered rings, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Sulfur may Heterocyclyl can be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclyl has zero or 5 one double bonds, non-aromatic 6- and 7-membered heterocyclyl groups have zero to two double bonds, and non-aromatic 8-membered heterocyclyl groups have zero to two double bonds and / or zero or one carbon-carbon triple bond. Heterocyclyl groups include from 1 to 16 carbon atoms unless otherwise specified. Certain heterocyclyl groups may include up to 9 carbon atoms. Non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, 10 imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, pyranyl, dihydropyranyl, and dithiazolyl. If the heterocyclic ring system has at least one aromatic resonance structure or at least one aromatic tautomer, such structure is an aromatic heterocyclyl (i.e., heteroaryl). Non-limiting 15 examples of heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, indolinyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, tetrahydroiso, quinolinyl tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydroquinolinyl), thiadiazolyl (e.g., 1,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, and tetrazolyl. The term “heterocyclyl” also 20 represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and / or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., quinuclidine, tropanes, or diaza-bicyclo[2.2.2]octane. The term “heterocyclyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, 25 a cyclopentene ring, or another monocyclic heterocyclic ring. Examples of fused heterocyclyls include 1,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3- dihydrobenzothiophene. The heterocyclyl group may be unsubstituted or substituted with one, two, three, four or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; 30 cycloalkyl alkyl; cycloalkyl alkynyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; heterocyclyl alkyl; heterocyclyl alkynyl; hydroxy; nitro; thiol; silyl; cyano; =O; =S; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group. 35 The term “heterocyclyl alkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group, each as defined herein. The heterocyclyl and alkyl portions may be optionally substituted as the individual groups described herein. The term “heterocyclyl alkynyl,” as used herein, represents an alkynyl group substituted with a heterocyclyl group, each as defined herein. The heterocyclyl and alkynyl portions may be optionally 40 substituted as the individual groups described herein. 30 PATENT ATTORNEY DOCKET: 51246-065WO2 The term “heterocyclylene,” as used herein, represents a divalent heterocyclyl. An optionally substituted heterocyclylene is a heterocyclylene that is optionally substituted as described herein for heterocyclyl. The term “(heterocyclyl)oxy,” as used herein, represents a chemical substituent of formula – 5 OR, where R is a heterocyclyl group, unless otherwise specified. (Heterocyclyl)oxy can be optionally substituted in a manner described for heterocyclyl. The terms “hydroxyl” and “hydroxy,” as used interchangeably herein, represent an -OH group. The term “isotopically enriched,” as used herein, refers to the pharmaceutically active agent with the isotopic content for one isotope at a predetermined position within a molecule that is at least 10 100 times greater than the natural abundance of this isotope. For example, a composition that is isotopically enriched for deuterium includes an active agent with at least one hydrogen atom position having at least 100 times greater abundance of deuterium than the natural abundance of deuterium. Preferably, an isotopic enrichment for deuterium is at least 1000 times greater than the natural abundance of deuterium. More preferably, an isotopic enrichment for deuterium is at least 4000 times 15 greater (e.g., at least 4750 times greater, e.g., up to 5000 times greater) than the natural abundance of deuterium. The term “leukemia,” as used herein, refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically 20 classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, e.g., acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic 25 granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphoma, lymphatic leukemia, 30 lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell 35 leukemia, subleukemic leukemia, and undifferentiated cell leukemia. The term “lymphoma,” as used herein, refers to a cancer arising from cells of immune origin. Non-limiting examples of T and B cell lymphomas include non-Hodgkin lymphoma and Hodgkin disease, diffuse large B-cell lymphoma, follicular lymphoma, mucosa-associated lymphatic tissue (MALT) lymphoma, small cell lymphocytic lymphoma-chronic lymphocytic leukemia, Mantle cell 40 lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma-Waldenstrom 31 PATENT ATTORNEY DOCKET: 51246-065WO2 macroglobulinemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL) / follicular T-cell lymphoma (FTCL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukaemia / lymphoma (ATLL), or extranodal NK / T-cell lymphoma, nasal type. 5 The term “melanoma,” as used herein, is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, e.g., acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and 10 superficial spreading melanoma. The term “nitro,” as used herein, represents an -NO2 group. The term “oxo,” as used herein, represents a divalent oxygen atom (e.g., the structure of oxo may be shown as =O). The term “PARP inhibitor,” as used herein, refers to a compound that, upon contacting PARP, 15 whether in vitro, in cell culture, or in an animal, reduces the activity of PARP, such that the measured PARP IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain PARP inhibitors, the PARP IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the PARP IC50 is 0.1 nM to 1 µM (e.g., 0.5 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM). 20 The term “PARP,” as used herein, refers to poly ADP ribose polymerase (PARP). The term “Ph,” as used herein, represents phenyl. The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein, formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic 25 regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein. 30 The term “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier,” as used interchangeably herein, refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), 35 emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, 40 gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, 32 PATENT ATTORNEY DOCKET: 51246-065WO2 maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, 5 vitamin E, vitamin C, and xylitol. The term “pharmaceutically acceptable salt,” as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For 10 example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, 15 aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, 20 pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, 25 dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The term “pharmacodynamic activity” as used herein refers to the ability of a drug or combination of drugs to perform a desired activity in a subject as part of a treatment. For example, a cancer therapy may involve the administration of a drug intended to reduces the viability of a cancer cell. The pharmacodynamic activity of that drug, therefore, is representative of the drug’s effect on the 30 viability of a cancer cell. In some embodiments, the pharmacodynamic activity of a drug is representative of the drug’s effect on a biological pathway. For example, the pharmacodynamic activity of an inhibitor (e.g., a Polθ inhibitor or a PARP inhibitor) may be representative of the inhibitor’s effect on a biological pathway including the target of the inhibitor (e.g., theta-mediated end joining or base excision repair). 35 The term “Polθ,” as used herein, refers to Human Polymerase theta. The term “Polθ inhibitor,” as used herein, represents a compound that reduces the activity of Polθ in a biochemical assay, such that the measured Polθ IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Polθ inhibitors, the Polθ IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the Polθ IC50 is 1 nM to 1 µM (e.g., 40 1 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM). 33 PATENT ATTORNEY DOCKET: 51246-065WO2 The term “Polθ inhibitor,” as used herein, also represents a compound that upon contacting a cell expressing Polθ reduces the activity of Polθ, such that the measured Polθ IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Polθ inhibitors, the Polθ IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the Polθ 5 IC50 is 1 nM to 1 µM (e.g., 1 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM). The term “Polθ inhibitor,” as used herein, may also represent a compound that upon contacting a cell reduces MMEJ or Alt-NHEJ activity. The term “Ροlθ overexpression” refers to the increased expression or activity of Ροlθ in a diseases cell e.g., cancerous cell, relative to expression or activity of Ροlθ in a normal cell (e.g., non- 10 diseased cell of the same kind). The amount of Ροlθ can be at least 2-fold, at least 3-fold, at least 4- fold, at least 5- fold, at least 10-fold, or more relative to the Ροlθ expression in a normal cell. Examples of Ροlθ cancers include, but are not limited to, breast, ovarian, cervical, lung, colorectal, gastric, bladder and prostate cancers. The term “pre-malignant” or “pre-cancerous,” as used herein, refers to a condition that is not 15 malignant but is poised to become malignant. Non-limiting examples of pre-malignant conditions include myelodysplastic syndrome, polyps in the colon, actinic keratosis of the skin, dysplasia of the cervix, metaplasia of the lung, and leukoplakia. The term “prodrug,” as used herein, refers to a compound which, when administered as a medicament, undergoes a conversion to a second compound. In some embodiments, the prodrug has 20 one or more beneficial properties for administration as a medicament (e.g., solubility, bioavailability, and stability) when compared to the second compound. In some embodiments, the second compound may exhibit a higher activity than the first compound. In some embodiments, a method of the present disclosure includes administration of a desired pharmaceutical as a prodrug. In some embodiments, a compound of the disclosure may be reformulated for administration as a prodrug. 25 The term “protecting group,” as used herein, represents a group intended to protect a hydroxy, an amino, or a carbonyl from participating in one or more undesirable reactions during chemical synthesis. The term “O-protecting group,” as used herein, represents a group intended to protect a hydroxy or carbonyl group from participating in one or more undesirable reactions during chemical synthesis. The term “N-protecting group,” as used herein, represents a group intended to 30 protect a nitrogen containing (e.g., an amino, amido, heterocyclic N-H, or hydrazine) group from participating in one or more undesirable reactions during chemical synthesis. Commonly used O- and N-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Exemplary O- and N-protecting groups include alkanoyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl,35 pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4'-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylpehenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl. Exemplary O-protecting groups for protecting carbonyl containing groups include, but are not 40 limited to: acetals, acylals, 1,3-dithianes, 1,3-dioxanes, 1,3-dioxolanes, and 1,3-dithiolanes. 34 PATENT ATTORNEY DOCKET: 51246-065WO2 Other O-protecting groups include, but are not limited to: substituted alkyl, aryl, and aryl-alkyl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2,- trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2- (trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p- 5 nitrophenyl, benzyl, p-methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and diphenymethylsilyl); carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4- dimethoxybenzyl; and nitrobenzyl). 10 Other N-protecting groups include, but are not limited to, chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine, and the like; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p bromobenzyloxycarbonyl, 3,4- 15 dimethoxybenzyloxycarbonyl, 3,5 dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4 methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5 trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5 dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, 20 allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl- 9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like, aryl-alkyl groups such as benzyl, p-methoxybenzyl, 2,4- dimethoxybenzyl, triphenylmethyl, benzyloxymethyl, and the like, silylalkylacetal groups such as [2- (trimethylsilyl)ethoxy]methyl and silyl groups such as trimethylsilyl, and the like. Useful N-protecting 25 groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, dimethoxybenzyl, [2-(trimethylsilyl)ethoxy]methyl (SEM), tetrahydropyranyl (THP), t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz). The term “tautomer” refers to structural isomers that readily interconvert, often by relocation of a proton. Tautomers are distinct chemical species that can be identified by differing spectroscopic 30 characteristics, but generally cannot be isolated individually. Non-limiting examples of tautomers include ketone - enol, enamine - imine, amide - imidic acid, nitroso - oxime, ketene – ynol, and amino acid – ammonium carboxylate. The term “sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar 35 or homogeneous substance. Non-limiting examples of sarcomas that may be treated with a compound or method provided herein include, e.g., a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy’s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, 40 stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, 35 PATENT ATTORNEY DOCKET: 51246-065WO2 granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and 5 telangiectaltic sarcoma. The term “stain” as used herein, refers to a material which enables CIP2A foci accumulation to be measured by an artisan. In some embodiments, a stain is a material which increases the image contrast (e.g., the signal difference between a target site in a cell (e.g., a target protein or focus thereof) and a site proximal thereto) of an image obtained from a visualization means. In some 10 embodiments, a stain may include a dye chemically bound or conjugated to a targeting moiety. The dye is a chemical group which provides a larger signal during a visualization experiment then either the target site or sites proximal thereto. For example, the dye may be a fluorescent compound which emits light when stimulated with excitation light (e.g., a fluorophore), and the target site and proximal site may be non-fluorescent. The targeting moiety is a chemical or biological group with an affinity for 15 the target site (e.g., a high binding affinity to a target protein), thereby localizing the stain (and therefore the dye) to the target site and increasing the image contrast. When the visualization means is immunostaining or immunohistochemistry, the targeting moiety is an antibody specific to the target protein. The term “subject,” as used herein, represents a human or non-human animal (e.g., a 20 mammal) that is suffering from, or is at risk of, disease or condition, as determined by a qualified professional (e.g., a doctor or a nurse practitioner) with or without known in the art laboratory test(s) of sample(s) from the subject. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases having the symptom of cell hyperproliferation, e.g., a cancer. “Treatment” and “treating,” as used herein, refer to the medical management of a subject with 25 the intent to improve, ameliorate, stabilize, prevent or cure a disease or condition. This term includes active treatment (treatment directed to improve the disease or condition); causal treatment (treatment directed to the cause of the associated disease or condition); palliative treatment (treatment designed for the relief of symptoms of the disease or condition); preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease or 30 condition); and supportive treatment (treatment employed to supplement another therapy). Description of the Drawings FIG.1A is a series of images that show representative micrographs of HCT116 WT or BRCA2-KO cells processed for pH3(S10) (a marker of mitotic chromosomes) and CIP2A 35 immunofluorescence with or without treatment with the Polθ inhibitor compound 431. FIG.1B a series of graphs that show the quantification of CIP2A foci per mitosis in HCT116 and DLD1 (WT or Polθ-KO, as indicated) cells with or without compound 431 treatment. Each point represents a mitotic cell; data from 3 independent experiments (≥50 cells manually scored per condition in each experiment) with mean (solid lines) 36 PATENT ATTORNEY DOCKET: 51246-065WO2 FIG.1C a series of graphs that show the quantification of CIP2A foci per mitosis in HCT116 BRCA2-KO and DLD1 BRCA2-KO cells with or without compound 431 treatment. Each point represents a mitotic cell; data from 3 independent experiments (≥50 cells manually scored per condition in each experiment) with mean (solid lines) 5 FIG.1D a series of graphs that show the percentage of CIP2A-high mitoses in HCT116 and DLD1 cells of indicated genotypes treated with indicated concentrations of compound 431. CIP2A- high mitoses are defined as pH3(S10)-positive cells with mean CIP2A nuclear intensity higher than the 90th percentile of untreated WT cells (as measured by automated image analysis). Data (open symbols) are mean of 3 independent experiments ±SD. IC50 values were determined by a non-linear 10 least square fit to a four-parameter dose-response model (solid lines). FIG.2A a series of images that show representative micrographs of HCT116 BRCA2-KO cells processed for pH3(S10) (a marker of mitotic chromosomes) and CIP2A immunofluorescence with or without treatment with the Polθ inhibitor compound 431, the PARP inhibitor AZD5305, or their combination. 15 FIG.2B is a graph that shows the percentage of mitotic HCT116 BRCA2-KO cells with >10 CIP2A foci with or without indicated treatments. Data from three independent experiments (open circles) with mean (bars) ±SD. FIG.3A a series of images that show representative micrographs of mitotic cells in HCT116 BRCA2-KO mouse subcutaneous xenograft tumors with or without 4-day treatment with the Polθ 20 inhibitor compound 431, the PARP inhibitor olaparib, or their combination. FFPE-fixed tissue sections were processed for immunofluorescence for p-H3(S10) (mitotic marker) and CIP2A. FIG.3B is a graph that shows the percentage of mitotic cells with >10 CIP2A foci in HCT116 BRCA2-KO mouse xenografts with or without indicated treatments. Data from three mice per condition (open circles) with mean (bars) ±SD. C. Mean volume (±SEM) of HCT116 BRCA2-KO 25 mouse xenograft tumors treated with vehicle, compound 431, olaparib, or their combination for the indicated amount of days. N=10 mice / group. FIG.3C is a graph that shows the volume of tumors over 75 days of treatment with vehicle alone, olaparib alone (administered at 25 mg / kg), compound 431 alone (administered at 60 mg / kg), and a combination therapy using olaparib (25 mg / kg) and a reduced dosage of compound 431 (10 30 mg / kg). Over the course of treatment, the combination therapy showed improvement in treatment efficacy over either monotherapy. FIG.4A a series of images of patient tumors (BRCA1 mutated ovarian cancer) at baseline (before Polθ inhibitor treatment), processed for immunofluorescence with anti-CIP2A and anti- H3pS10 (pH3) antibodies. Overlap of CIP2A and pH3 signal is shown on left panels, isolated CIP2A 35 signal is on the right. Solid line circles denote pH3-positive regions. FIG.4B a series of images of patient tumors (BRCA1 mutated ovarian cancer) after Polθ inhibitor treatment with compound 431, processed for immunofluorescence with anti-CIP2A and anti- H3pS10 (pH3) antibodies. Overlap of CIP2A and pH3 signal is shown on left panels, isolated CIP2A signal is on the right. Solid line circles denote pH3-positive regions. 37 PATENT ATTORNEY DOCKET: 51246-065WO2 FIG.5 is a graph showing the quantification of the pH3-positive cells showing ≥10 CIP2A foci (CIP2A+) in the samples shown in FIG.4A and FIG.4B (see Example 4). Detailed Description of the Invention 5 In general, the invention provides methods of measuring the pharmacodynamic activity of inhibitors of DNA replication associated proteins (e.g., human polymerase theta (Polθ) and poly(ADP- ribose) polymerase (PARP)) by measuring the focal accumulation of the cancerous inhibitor of protein phosphatase 2A (CIP2A) protein. Successful clinical development of drug candidates requires a measurement of their 10 pharmacodynamic activity. Polθ inhibitors require a specific and sensitive readout of their pharmacodynamic (PD) activity. The main function of Polθ is to facilitate an error-prone DNA break repair pathway called theta- (or microhomology-) mediated end joining (TMEJ / MMEJ) – an error- prone mechanism characterized by microhomologies and frequent indel mutations surrounding the DNA breakpoint. While feasible pre-clinically, directly monitoring TMEJ activity is impractical in a 15 clinical setting, as it requires specialized cellular reporter systems. As such, there is a growing need for development of novel PD assays for Polθ inhibitors. Polθ and TMEJ are uniquely active in cells undergoing mitosis. Monitoring unrepaired DNA breaks in mitosis could therefore provide a readout of Polθ inhibition. The method described herein utilizes immunofluorescence or immunochemistry to quantify mitotic DNA breaks marked by focal 20 accumulation of the protein CIP2A (cancerous inhibitor of protein phosphatase 2A) on mitotic chromosomes. The increase in nuclear CIP2A foci as a readout of Polθ inhibitors activity can be observed on cultured cells and FFPE-fixed tissue sections, both in HR-proficient and in HR-deficient cells, and after single-agent treatment with Polθ inhibitors as well as in combination with PARP inhibitors. The CIP2A assay therefore provides a novel, clinically translatable PD marker for Polθ 25 inhibitors. Polθ Inhibitors The methods of the present disclosure may be used to determine the pharmacodynamic activity of a Polθ inhibitor, or the efficacy of treating a disease or disorder therewith. By measuring a 30 signal intensity (e.g., a fluorescence intensity) methods of the present disclosure allow for the detection of pharmacodynamic activity at low concentrations of the inhibitor. In some embodiments, methods of the present disclosure include measuring a CIP2A signal intensity by measuring a fluorescence signal in an immunofluorescence assay, wherein the fluorescence signal is proportional to CIP2A foci accumulation. The fluorescence signal and CIP2A foci accumulation is proportional to 35 the pharmacodynamic activity of a Polθ inhibitor. In some embodiments, the Polθ inhibitor may be, e.g., a compound of formula (I): or a pharmaceutically acceptable salt thereof, 38 PATENT ATTORNEY DOCKET: 51246-065WO2 wherein V is N or CR; W is optionally substituted C1-6 alkylene, C1-6 alkoxyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 5 aryl; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C1-6 alkylene, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted allenyl, optionally substituted C2-6 alkynyl, optionally10 substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3- 8 cycloalkylene, RXis amino, halo, optionally substituted C1-6 alkoxyl, optionally substituted acyl, carboxyl, amido, optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or 15 optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, halo, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, 20 optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, optionally substituted C2-6 alkenyl, acyl, or amido; and R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally 25 substituted C3-8 cycloalkyl. The compound evaluated by the methods of the invention may be, e.g., a compound of formula (II): 30 or a pharmaceutically acceptable salt thereof. The compound evaluated by the methods of the invention may be, e.g., a compound of formula (III): 35 or a pharmaceutically acceptable salt thereof. 39 PATENT ATTORNEY DOCKET: 51246-065WO2 The compound evaluated by the methods of the invention may be, e.g., a compound of formula (IV): 5 or a pharmaceutically acceptable salt thereof. The compound evaluated by the methods of the invention may be, e.g., a compound of formula (V): 10 or a pharmaceutically acceptable salt thereof. The compound evaluated by the methods of the invention may be, e.g., a compound of formula (VI): , 15 or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl or a C4-C9 heterocyclyl optionally substituted with oxo; 20 RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH. 25 Advantageously, compounds disclosed herein may exhibit superior stability (e.g., microsomal stability) and / or superior metabolic profiles (e.g., reduced CYP3A4 inhibition or reduced PXR activation) relative to the compounds in which the thiazole or thiadiazole core is bonded to an oxygen atom at the position proximal to the endocyclic sulfur atom. The compound evaluated by the methods of the invention may be, e.g., a compound of 30 formula (VII): 40 PATENT ATTORNEY DOCKET: 51246-065WO2 , or a pharmaceutically acceptable salt thereof, wherein 5 n is 0 or 1; o is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl, C1-C6 perfluoroalkyl, halo, or a C4-C9 heterocyclyl optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; 10 RA3is hydrogen or a halogen; RA4is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-C9 cycloalkyl, optionally substituted C3-C9 heterocyclylene, halo, trifluoromethyl, CN, or optionally substituted C2-9 heteroarylene; or the bond between RA4and the cycloalkyl is an alkene; 15 each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH. In some embodiments, the compound evaluated by the methods of the invention may be a prodrug which is converted to the active drug in vivo. In some embodiments, the methods of the 20 present disclosure includes determining the pharmacodynamic activity of a Polθ inhibitor formulated as a prodrug, or the efficacy of treating a disease or disorder with a Polθ inhibitor formulated as a prodrug. In some embodiments, the Polθ prodrug is a compound of formula (PI) 25 (PI), or a pharmaceutically acceptable salt thereof wherein: is an alkene of either E or Z isomeric configuration; V is N or CR; 41 PATENT ATTORNEY DOCKET: 51246-065WO2 W is optionally substituted C1-6 alkylene, C1-6 alkoxyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or 5 optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C1-6 alkylene, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted allenyl, optionally substituted C2-6 alkynyl, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3- 8 cycloalkylene, RXis amino, halo, optionally substituted C1-6 alkoxyl, optionally substituted acyl, 10 carboxyl, amido, optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally 15 substituted C6-10 aryl; Z is a H, halo, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, optionally substituted C2-6 alkenyl, acyl, or amido; 20 R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl; and M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 25 alkylacylphosphonyl, –RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is independently optionally substituted C1-6 alkyl, and each RM2is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl. In some embodiments, the Polθ prodrug is a compound of formula (PIIa) , 30 (PIIa) or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ prodrug is a compound of formula (PIIb): , 35 or a pharmaceutically acceptable salt thereof. 42 PATENT ATTORNEY DOCKET: 51246-065WO2 In some embodiments, the Polθ prodrug is a compound of formula (PIIIa) , or a pharmaceutically acceptable salt thereof. 5 In some embodiments, the Polθ prodrug is a compound of formula (PIIIb): , or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ prodrug is a compound of formula (PIVa): 10 , or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ prodrug is a compound of formula (PIVb): , 15 or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ prodrug is a compound of formula (PVa) , 20 or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ prodrug is a compound of formula (PVb): , 43 PATENT ATTORNEY DOCKET: 51246-065WO2 or a pharmaceutically acceptable salt thereof. In some embodiments, the Polθ prodrug is a compound of formula (PVIa): , 5 or a pharmaceutically acceptable salt thereof, wherein is an alkene of either E or Z isomeric configuration; n is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl or a C4-C9 heterocyclyl 10 optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or 15 CH. In some embodiments, the Polθ prodrug is a compound of formula (PVIb) , or a pharmaceutically acceptable salt thereof. 20 In some embodiments, the Polθ prodrug is a compound of formula (PVIIa): 44 PATENT ATTORNEY DOCKET: 51246-065WO2 , or a pharmaceutically acceptable salt thereof, wherein 5 is an alkene of either E or Z isomeric configuration; n is 0 or 1; o is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl, C1-C6 perfluoroalkyl, halo, or a C4-C9 heterocyclyl optionally substituted with oxo; 10 RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; RA4is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-C9 cycloalkyl, optionally substituted C3-C9 heterocyclylene, halo, trifluoromethyl, CN, or optionally substituted C2-9 heteroarylene; or 15 the bond between RA4and the cycloalkyl is an alkene; each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH. In some embodiments, the Polθ prodrug is a compound of formula (PVIIb): 20 , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound evaluated by the methods of the invention may be, e.g., a compound listed in Table 1 below or a pharmaceutically acceptable salt thereof. 25 45 PATENT ATTORNEY DOCKET: 51246-065WO2 Table 1 46 PATENT ATTORNEY DOCKET: 51246-065WO2 47 PATENT ATTORNEY DOCKET: 51246-065WO2 48 PATENT ATTORNEY DOCKET: 51246-065WO2 49 PATENT ATTORNEY DOCKET: 51246-065WO2 50 PATENT ATTORNEY DOCKET: 51246-065WO2 51 PATENT ATTORNEY DOCKET: 51246-065WO2 52 PATENT ATTORNEY DOCKET: 51246-065WO2 53 PATENT ATTORNEY DOCKET: 51246-065WO2 54 PATENT ATTORNEY DOCKET: 51246-065WO2 55 PATENT ATTORNEY DOCKET: 51246-065WO2 56 PATENT ATTORNEY DOCKET: 51246-065WO2 57 PATENT ATTORNEY DOCKET: 51246-065WO2 58 PATENT ATTORNEY DOCKET: 51246-065WO2 59 PATENT ATTORNEY DOCKET: 51246-065WO2 60 PATENT ATTORNEY DOCKET: 51246-065WO2 61 PATENT ATTORNEY DOCKET: 51246-065WO2 62 PATENT ATTORNEY DOCKET: 51246-065WO2 63 PATENT ATTORNEY DOCKET: 51246-065WO2 64 PATENT ATTORNEY DOCKET: 51246-065WO2 65 PATENT ATTORNEY DOCKET: 51246-065WO2 66 PATENT ATTORNEY DOCKET: 51246-065WO2 67 PATENT ATTORNEY DOCKET: 51246-065WO2 68 PATENT ATTORNEY DOCKET: 51246-065WO2 69 PATENT ATTORNEY DOCKET: 51246-065WO2 70 PATENT ATTORNEY DOCKET: 51246-065WO2 71 PATENT ATTORNEY DOCKET: 51246-065WO2 72 PATENT ATTORNEY DOCKET: 51246-065WO2 73 PATENT ATTORNEY DOCKET: 51246-065WO2 74 PATENT ATTORNEY DOCKET: 51246-065WO2 75 PATENT ATTORNEY DOCKET: 51246-065WO2 76 PATENT ATTORNEY DOCKET: 51246-065WO2 77 PATENT ATTORNEY DOCKET: 51246-065WO2 78 PATENT ATTORNEY DOCKET: 51246-065WO2 79 PATENT ATTORNEY DOCKET: 51246-065WO2 80 PATENT ATTORNEY DOCKET: 51246-065WO2 81 PATENT ATTORNEY DOCKET: 51246-065WO2 82 PATENT ATTORNEY DOCKET: 51246-065WO2 83 PATENT ATTORNEY DOCKET: 51246-065WO2 84 PATENT ATTORNEY DOCKET: 51246-065WO2 85 PATENT ATTORNEY DOCKET: 51246-065WO2 86 PATENT ATTORNEY DOCKET: 51246-065WO2 87 PATENT ATTORNEY DOCKET: 51246-065WO2 88 PATENT ATTORNEY DOCKET: 51246-065WO2 89 PATENT ATTORNEY DOCKET: 51246-065WO2 90 PATENT ATTORNEY DOCKET: 51246-065WO2 91 PATENT ATTORNEY DOCKET: 51246-065WO2 92 PATENT ATTORNEY DOCKET: 51246-065WO2 93 PATENT ATTORNEY DOCKET: 51246-065WO2 94 PATENT ATTORNEY DOCKET: 51246-065WO2 95 PATENT ATTORNEY DOCKET: 51246-065WO2 96 PATENT ATTORNEY DOCKET: 51246-065WO2 97 PATENT ATTORNEY DOCKET: 51246-065WO2 98 PATENT ATTORNEY DOCKET: 51246-065WO2 99 PATENT ATTORNEY DOCKET: 51246-065WO2 100 PATENT ATTORNEY DOCKET: 51246-065WO2 101 PATENT ATTORNEY DOCKET: 51246-065WO2 102 PATENT ATTORNEY DOCKET: 51246-065WO2 103 PATENT ATTORNEY DOCKET: 51246-065WO2 Other Polθ inhibitors for use in the invention include those in International Patent Publication Nos: WO 2020 / 243459; WO 2020 / 160213; WO 2022 / 026548; WO 2022 / 118210; WO 2022 / 026565; WO 2022 / 259204; WO 2023 / 067515; WO 2023 / 233295; WO 2023 / 217095; WO 2023 / 241322; WO 5 2024 / 076964; WO 2023 / 060573; WO 2023 / 061415; WO 2023 / 134708; WO2023 / 067353, WO 2023 / 067354; WO 2023 / 067355; WO 2023 / 067356; and WO 2024 / 069592, the Polθ inhibitors of which are incorporated herein by reference. Exemplary Polθ inhibitors include those in Table 2. Table 2 104 PATENT ATTORNEY DOCKET: 51246-065WO2 105 PATENT ATTORNEY DOCKET: 51246-065WO2 106 PATENT ATTORNEY DOCKET: 51246-065WO2 107 PATENT ATTORNEY DOCKET: 51246-065WO2 108 PATENT ATTORNEY DOCKET: 51246-065WO2 109 PATENT ATTORNEY DOCKET: 51246-065WO2 110 PATENT ATTORNEY DOCKET: 51246-065WO2 111 PATENT ATTORNEY DOCKET: 51246-065WO2 112 PATENT ATTORNEY DOCKET: 51246-065WO2 113 PATENT ATTORNEY DOCKET: 51246-065WO2 114 PATENT ATTORNEY DOCKET: 51246-065WO2 115 PATENT ATTORNEY DOCKET: 51246-065WO2 116 PATENT ATTORNEY DOCKET: 51246-065WO2 117 PATENT ATTORNEY DOCKET: 51246-065WO2 118 PATENT ATTORNEY DOCKET: 51246-065WO2 119 PATENT ATTORNEY DOCKET: 51246-065WO2 120 PATENT ATTORNEY DOCKET: 51246-065WO2 121 PATENT ATTORNEY DOCKET: 51246-065WO2 122 PATENT ATTORNEY DOCKET: 51246-065WO2 123 PATENT ATTORNEY DOCKET: 51246-065WO2 124 PATENT ATTORNEY DOCKET: 51246-065WO2 125 PATENT ATTORNEY DOCKET: 51246-065WO2 126 PATENT ATTORNEY DOCKET: 51246-065WO2 127 PATENT ATTORNEY DOCKET: 51246-065WO2 128 PATENT ATTORNEY DOCKET: 51246-065WO2 129 PATENT ATTORNEY DOCKET: 51246-065WO2 130 PATENT ATTORNEY DOCKET: 51246-065WO2 131 PATENT ATTORNEY DOCKET: 51246-065WO2 132 PATENT ATTORNEY DOCKET: 51246-065WO2 133 PATENT ATTORNEY DOCKET: 51246-065WO2 134 PATENT ATTORNEY DOCKET: 51246-065WO2 135 PATENT ATTORNEY DOCKET: 51246-065WO2 136 PATENT ATTORNEY DOCKET: 51246-065WO2 137 PATENT ATTORNEY DOCKET: 51246-065WO2 138 PATENT ATTORNEY DOCKET: 51246-065WO2 139 PATENT ATTORNEY DOCKET: 51246-065WO2 140 PATENT ATTORNEY DOCKET: 51246-065WO2 141 PATENT ATTORNEY DOCKET: 51246-065WO2 142 PATENT ATTORNEY DOCKET: 51246-065WO2 143 PATENT ATTORNEY DOCKET: 51246-065WO2 144 PATENT ATTORNEY DOCKET: 51246-065WO2 145 PATENT ATTORNEY DOCKET: 51246-065WO2 146 PATENT ATTORNEY DOCKET: 51246-065WO2 147 PATENT ATTORNEY DOCKET: 51246-065WO2 148 PATENT ATTORNEY DOCKET: 51246-065WO2 149 PATENT ATTORNEY DOCKET: 51246-065WO2 150 PATENT ATTORNEY DOCKET: 51246-065WO2 151 PATENT ATTORNEY DOCKET: 51246-065WO2 152 PATENT ATTORNEY DOCKET: 51246-065WO2 153 PATENT ATTORNEY DOCKET: 51246-065WO2 154 PATENT ATTORNEY DOCKET: 51246-065WO2 155 PATENT ATTORNEY DOCKET: 51246-065WO2 156 PATENT ATTORNEY DOCKET: 51246-065WO2 157 PATENT ATTORNEY DOCKET: 51246-065WO2 158 PATENT ATTORNEY DOCKET: 51246-065WO2 159 PATENT ATTORNEY DOCKET: 51246-065WO2 PARP Inhibitors The methods of the present disclosure may be used to determine the pharmacodynamic activity of a PARP inhibitor, or the efficacy of treating a disease or disorder therewith. By measuring a 5 signal intensity (e.g., a fluorescence intensity) methods of the present disclosure allow for the 160 PATENT ATTORNEY DOCKET: 51246-065WO2 detection of pharmacodynamic activity at low concentrations of the PARP inhibitor. In some embodiments, methods of the present disclosure include measuring a CIP2A signal intensity by measuring a fluorescence signal in an assay an immunofluorescence assay, wherein the fluorescence signal is proportional to CIP2A foci accumulation. In some embodiments, the 5 fluorescence signal and CIP2A foci accumulation is proportional to the pharmacodynamic activity of a PARP inhibitor. PARP inhibitors for use in the methods of the invention include those disclosed in PARP inhibitors include, e.g., those described in U.S. Patent Nos.8,716,493; 8,236,802; 8,071,623; 8,012,976; 7,732,491; 7,550,603; 7,531,530; 7,151,102; and 6,495,541; and those described in 10 International Patent Publication Nos. WO 2022 / 225934; WO 2023 / 025307; WO 2022 / 218296; WO 2022 / 235585; WO 2022 / 228387; WO 2022 / 247816; WO 2022 / 222966; WO2024082654 , WO2024083218 , WO2024067691, WO2024046366 , WO2024050370 , WO2024046420 , WO2024041643 , WO2023212219 , WO2023207284 , and WO2023207283, the PARP inhibitors of which are incorporated herein by reference herein. Exemplary PARP inhibitors include those in Table 15 3. Table 3 161 PATENT ATTORNEY DOCKET: 51246-065WO2 2 3 162 PATENT ATTORNEY DOCKET: 51246-065WO2 163 PATENT ATTORNEY DOCKET: 51246-065WO2 164 PATENT ATTORNEY DOCKET: 51246-065WO2 165 PATENT ATTORNEY DOCKET: 51246-065WO2 166 PATENT ATTORNEY DOCKET: 51246-065WO2 167 PATENT ATTORNEY DOCKET: 51246-065WO2 168 PATENT ATTORNEY DOCKET: 51246-065WO2 169 PATENT ATTORNEY DOCKET: 51246-065WO2 170 PATENT ATTORNEY DOCKET: 51246-065WO2 171 PATENT ATTORNEY DOCKET: 51246-065WO2 172 PATENT ATTORNEY DOCKET: 51246-065WO2 173 PATENT ATTORNEY DOCKET: 51246-065WO2 174 PATENT ATTORNEY DOCKET: 51246-065WO2 175 PATENT ATTORNEY DOCKET: 51246-065WO2 176 PATENT ATTORNEY DOCKET: 51246-065WO2 177 PATENT ATTORNEY DOCKET: 51246-065WO2 178 PATENT ATTORNEY DOCKET: 51246-065WO2 179 PATENT ATTORNEY DOCKET: 51246-065WO2 180 PATENT ATTORNEY DOCKET: 51246-065WO2 181 PATENT ATTORNEY DOCKET: 51246-065WO2 182 PATENT ATTORNEY DOCKET: 51246-065WO2 183 PATENT ATTORNEY DOCKET: 51246-065WO2 184 PATENT ATTORNEY DOCKET: 51246-065WO2 185 PATENT ATTORNEY DOCKET: 51246-065WO2 186 PATENT ATTORNEY DOCKET: 51246-065WO2 187 PATENT ATTORNEY DOCKET: 51246-065WO2 188 PATENT ATTORNEY DOCKET: 51246-065WO2 189 PATENT ATTORNEY DOCKET: 51246-065WO2 190 PATENT ATTORNEY DOCKET: 51246-065WO2 191 PATENT ATTORNEY DOCKET: 51246-065WO2 192 PATENT ATTORNEY DOCKET: 51246-065WO2 193 PATENT ATTORNEY DOCKET: 51246-065WO2 194 PATENT ATTORNEY DOCKET: 51246-065WO2 195 PATENT ATTORNEY DOCKET: 51246-065WO2 196 PATENT ATTORNEY DOCKET: 51246-065WO2 197 PATENT ATTORNEY DOCKET: 51246-065WO2 198 PATENT ATTORNEY DOCKET: 51246-065WO2 199 PATENT ATTORNEY DOCKET: 51246-065WO2 200 PATENT ATTORNEY DOCKET: 51246-065WO2 201 PATENT ATTORNEY DOCKET: 51246-065WO2 202 PATENT ATTORNEY DOCKET: 51246-065WO2 203 PATENT ATTORNEY DOCKET: 51246-065WO2 204 PATENT ATTORNEY DOCKET: 51246-065WO2 205 PATENT ATTORNEY DOCKET: 51246-065WO2 206 PATENT ATTORNEY DOCKET: 51246-065WO2 207 PATENT ATTORNEY DOCKET: 51246-065WO2 208 PATENT ATTORNEY DOCKET: 51246-065WO2 209 PATENT ATTORNEY DOCKET: 51246-065WO2 210 PATENT ATTORNEY DOCKET: 51246-065WO2 211 PATENT ATTORNEY DOCKET: 51246-065WO2 212 PATENT ATTORNEY DOCKET: 51246-065WO2 213 PATENT ATTORNEY DOCKET: 51246-065WO2 214 PATENT ATTORNEY DOCKET: 51246-065WO2 215 PATENT ATTORNEY DOCKET: 51246-065WO2 216 PATENT ATTORNEY DOCKET: 51246-065WO2 217 PATENT ATTORNEY DOCKET: 51246-065WO2 218 PATENT ATTORNEY DOCKET: 51246-065WO2 219 PATENT ATTORNEY DOCKET: 51246-065WO2 220 PATENT ATTORNEY DOCKET: 51246-065WO2 221 PATENT ATTORNEY DOCKET: 51246-065WO2 222 PATENT ATTORNEY DOCKET: 51246-065WO2 223 PATENT ATTORNEY DOCKET: 51246-065WO2 224 PATENT ATTORNEY DOCKET: 51246-065WO2 225 PATENT ATTORNEY DOCKET: 51246-065WO2 226 PATENT ATTORNEY DOCKET: 51246-065WO2 227 PATENT ATTORNEY DOCKET: 51246-065WO2 228 PATENT ATTORNEY DOCKET: 51246-065WO2 229 PATENT ATTORNEY DOCKET: 51246-065WO2 230 PATENT ATTORNEY DOCKET: 51246-065WO2 231 PATENT ATTORNEY DOCKET: 51246-065WO2 232 PATENT ATTORNEY DOCKET: 51246-065WO2 233 PATENT ATTORNEY DOCKET: 51246-065WO2 234 PATENT ATTORNEY DOCKET: 51246-065WO2 235 PATENT ATTORNEY DOCKET: 51246-065WO2 236 PATENT ATTORNEY DOCKET: 51246-065WO2 237 PATENT ATTORNEY DOCKET: 51246-065WO2 238 PATENT ATTORNEY DOCKET: 51246-065WO2 239 PATENT ATTORNEY DOCKET: 51246-065WO2 240 PATENT ATTORNEY DOCKET: 51246-065WO2 241 PATENT ATTORNEY DOCKET: 51246-065WO2 242 PATENT ATTORNEY DOCKET: 51246-065WO2 Further PARP inhibitors include DSB1559, EIK1003, HRS-1167, HS-10502, LAE119, SNV1521. A PARP inhibitor may be isotopically enriched (e.g., enriched for deuterium). 5 Pharmaceutical Compositions A compound for use in a method of the present invention may be formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include a compound as described herein and a pharmaceutically acceptable excipient. Certain pharmaceutical compositions 10 may include one or more additional pharmaceutically active agents described herein. The compounds described herein can also be used in the form of the free base, in the form of salts, zwitterions, solvates, or as prodrugs, or pharmaceutical compositions thereof. All forms are within the scope of the invention. The compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof, may be administered to a patient in a variety of forms 15 depending on the selected route of administration, as will be understood by those skilled in the art. The compounds used in the methods described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, 243 PATENT ATTORNEY DOCKET: 51246-065WO2 and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. For human use, a compound of the invention can be administered alone or in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard 5 pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present invention thus can be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries that facilitate processing of a compound of the invention into preparations which can be used pharmaceutically. This invention also includes pharmaceutical compositions which can contain one or more 10 pharmaceutically acceptable carriers. In making the pharmaceutical compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of 15 tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending upon the intended route of administration. The resulting compositions can include additional agents, e.g., preservatives. The excipient or carrier is selected based on the mode and route of administration. Suitable 20 pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP / NF (United States Pharmacopeia and the National Formulary). Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, 25 tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents, e.g., talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents, e.g., methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, Rowe et 30 al., Eds., Pharmaceutical Press (2009). These pharmaceutical compositions can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., 35 Lippincott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York. Proper formulation is dependent upon the route of administration chosen. The formulation and preparation of such compositions is well-known to those skilled in the art of pharmaceutical formulation. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the 40 other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of 244 PATENT ATTORNEY DOCKET: 51246-065WO2 less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh. 5 Dosages The dosage of the compound used in the methods described herein, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof, can vary depending on many factors, e.g., the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the 10 treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds used in the methods described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the 15 lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Combinations Methods of the invention include the measurement of the pharmacodynamic activity of a 20 combination of two or more treatment agents. In some embodiments the two or more treatment agents include a Polθ inhibitor and a PARP inhibitor. In some embodiments, the method includes the measurement of the pharmacodynamic activity combination therapy including a Polθ inhibitor or a PARP inhibitor, and one or more additional agents, e.g.,: (a) a cytotoxic agent; 25 (b) an antimetabolite; (c) an alkylating agent; (d) an anthracycline; (e) an antibiotic; (f) an anti-mitotic agent; 30 (g) a hormone therapy; (h) a signal transduction inhibitor; (i) a gene expression modulator; (j) an apoptosis inducer; (k) an angiogenesis inhibitor; 35 (l) an immunotherapy agent; (m) a DNA damage repair inhibitor; (n) a kinase inhibitor (o) a PARP inhibitor (p) an ionizing radiation therapy 40 (q) a radioligand therapy 245 PATENT ATTORNEY DOCKET: 51246-065WO2 (r) antibody drug conjugate (ADC) or a combination thereof. The cytotoxic agent may be, e.g., actinomycin-D, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, amphotericin, amsacrine, arsenic trioxide, asparaginase, azacitidine, 5 azathioprine, Bacille Calmette-Guérin (BCG), bendamustine, bexarotene, bevacuzimab, bleomycin, bortezomib, busulphan, capecitabine, carboplatin, carfilzomib, carmustine, cetuximab, cisplatin, chlorambucil, cladribine, clofarabine, colchicine, crisantaspase, cyclophosphamide, cyclosporine, cytarabine, cytochalasin B, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, 1- dehydrotestosterone, denileukin, dexamethasone, dexrazoxane, dihydroxy anthracin dione, 10 disulfiram, docetaxel, doxorubicin, emetine, epirubicin, erlotinib, epigallocatechin gallate, epoetin alfa, estramustine, ethidium bromide, etoposide, everolimus, filgrastim, finasunate, floxuridine, fludarabine, flurouracil (5-FU), fulvestrant, ganciclovir, geldanamycin, gemcitabine, glucocorticoids, gramicidin D, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib, irinotecan, interferons, interferon alfa-2a, interferon alfa-2b, ixabepilone, lactate dehydrogenase A (LDH-A), lenalidomide,15 letrozole, leucovorin, levamisole, lidocaine, lomustine, mechlorethamine, melphalan, 6- mercaptopurine, mesna, methotrexate, methoxsalen, metoprine, metronidazole, mithramycin, mitomycin-C, mitoxantrone, nandrolone, nelarabine, nilotinib, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, pemetrexed, pentostatin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, procaine, procarbazine, 20 propranolol, puromycin, quinacrine, radicicol, radioactive isotopes, raltitrexed, rapamycin, rasburicase, salinosporamide A, sargramostim, sunitinib, temozolomide, teniposide, tetracaine, 6-thioguanine, thiotepa, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, zoledronate, or a combination thereof. The antimetabolite may be, e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 25 5-fluorouracil decarbazine, cladribine, pemetrexed, gemcitabine, capecitabine, hydroxyurea, mercaptopurine, fludarabine, pralatrexate, clofarabine, cytarabine, decitabine, floxuridine, nelarabine, trimetrexate, thioguanine, pentostatin, or a combination thereof. The alkylating agent may be, e.g., mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, 30 streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin, altretamine, cyclophosphamide, ifosfamide, hexamethylmelamine, altretamine, procarbazine, dacarbazine, temozolomide, streptozocin, carboplatin, cisplatin, oxaliplatin, uramustine, bendamustine, trabectedin, semustine, or a combination thereof. The anthracycline may be, e.g., daunorubicin, doxorubicin, aclarubicin, aldoxorubicin, 35 amrubicin, annamycin, carubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, or a combination thereof. The antibiotic may be, e.g., dactinomycin, bleomycin, mithramycin, anthramycin (AMC), ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, piperacillin, pivampicillin, pivmecillinam, ticarcillin, aztreonam, imipenem, doripenem, 40 ertapenem, meropenem, cephalosporins, clarithromycin, dirithromycin, roxithromycin, telithromycin, 246 PATENT ATTORNEY DOCKET: 51246-065WO2 lincomycin, pristinamycin, quinupristin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, tobramycin, streptomycin, sulfamethizole, sulfamethoxazole, sulfisoxazole, demeclocycline, minocycline, oxytetracycline, tetracycline, penicillin, amoxicillin, cephalexin, erythromycin, clarithromycin, azithromycin, ciprofloxacin, levofloxacin, ofloxacin, doxycycline, 5 clindamycin, metronidazole, tigecycline, chloramphenicol, metronidazole, tinidazole, nitrofurantoin, vancomycin, teicoplanin, telavancin, linezolid, cycloserine, rifamycins, polymyxin B, bacitracin, viomycin, capreomycin, quinolones, daunorubicin, doxorubicin, 4’-deoxydoxorubicin, epirubicin, idarubicin, plicamycin, mitomycin-c, mitoxantrone, or a combination thereof. The anti-mitotic agent may be, e.g., vincristine, vinblastine, vinorelbine, docetaxel, 10 estramustine, ixabepilone, paclitaxel, maytansinoid, a dolastatin, a cryptophycin, or a combination thereof. The signal transduction inhibitor may be, e.g., imatinib, trastuzumab, erlotinib, sorafenib, sunitinib, temsirolimus, vemurafenib, lapatinib, bortezomib, cetuximab panitumumab, matuzumab, gefitinib, STI 571, rapamycin, flavopiridol, imatinib mesylate, vatalanib, semaxinib, motesanib, axitinib, 15 afatinib, bosutinib, crizotinib, cabozantinib, dasatinib, entrectinib, pazopanib, lapatinib, vandetanib, or a combination thereof. The gene expression modulator may be, e.g., a siRNA, a shRNA, an antisense oligonucleotide, an HDAC inhibitor, or a combination thereof. An HDAC inhibitor may be, e.g., trichostatin A, trapoxin B, valproic acid, vorinostat, belinostat, LAQ824, panobinostat, entinostat, 20 tacedinaline, mocetionstat, givinostat, resminostat, abexinostat, quisinostat, rocilinostat, practinostat, CHR-3996, butyric acid, phenylbutyric acid, 4SC202, romidepsin, sirtinol, cambinol, EX-527, nicotinamide, or a combination thereof. An antisense oligonucleotide may be, e.g., custirsen, apatorsen, AZD9150, trabadersen, EZN-2968, LErafAON-ETU, or a combination thereof. An siRNA may be, e.g., ALN-VSP, CALAA-01, Atu-027, SPC2996, or a combination thereof. 25 The hormone therapy may be, e.g., a luteinizing hormone-releasing hormone (LHRH) antagonist. The hormone therapy may be, e.g., firmagon, leuproline, goserelin, buserelin, flutamide, bicalutadmide, ketoconazole, aminoglutethimide, prednisone, hydroxyl-progesterone caproate, medroxy-progesterone acetate, megestrol acetate, diethylstil-bestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, raloxifene, droloxifene, iodoxyfene, 4- 30 hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, toremifine citrate, megestrol acetate, exemestane, fadrozole, vorozole, letrozole, anastrozole, nilutamide, tripterelin, histerelin, arbiraterone, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, tretinoin, fenretinide, troxacitabine, or a combination thereof. The apoptosis inducers may be, e.g., a recombinant human TNF-related apoptosis-inducing 35 ligand (TRAIL), camptothecin, bortezomib, etoposide, tamoxifen, or a combination thereof. The angiogenesis inhibitors may be, e.g., sorafenib, sunitinib, pazopanib, everolimus or a combination thereof. The immunotherapy agent may be, e.g., a monoclonal antibody, cancer vaccine (e.g., a dendritic cell (DC) vaccine), oncolytic virus, cytokine, adoptive T cell therapy, Bacille Calmette-Guérin 40 (BCG), GM-CSF, thalidomide, lenalidomide, pomalidomide, imiquimod, or a combination thereof. The 247 PATENT ATTORNEY DOCKET: 51246-065WO2 monoclonal antibody may be, e.g., anti-CTLA4, anti-PD1, anti-PD-L1, anti-LAG3, anti-KIR, or a combination thereof. The monoclonal antibody may be, e.g., alemtuzumab, trastuzumab, ibritumomab tiuxetan, brentuximab vedotin, trastuzumab, ado-trastuzumab emtansine, blinatumomab, bevacizumab, cetuximab, pertuzumab, panitumumab, ramucirumab, obinutuzumab, ofatumumab, 5 rituximab, pertuzumab, tositumomab, gemtuzumab ozogamicin, tositumomab, or a combination thereof. The cancer vaccine may be, e.g., Sipuleucel-T, BioVaxID, NeuVax, DCVax, SuVaxM, CIMAvax®, Provenge,®, hsp110 chaperone complex vaccine, CDX-1401, MIS416, CDX-110, GVAX Pancreas, HyperAcute™ Pancreas, GTOP-99 (MyVax®), or Imprime PGG®. The oncolytic virus may be, e.g., talimogene laherparepvec. The cytokine may be, e.g., IL-2, IFNα, or a combination thereof. 10 The adoptive T cell therapy may be, e.g., tisagenlecleucel, axicabtagene ciloleucel, or a combination thereof. The DNA damage repair inhibitor may be, e.g., a PARP inhibitor, a DNA-PK inhibitor, a cell checkpoint kinase inhibitor, or a combination thereof. The PARP inhibitor may be, e.g., olaparib, rucaparib, veliparib (ABT-888), niraparib (ZL-2306), iniparib (BSI-201), talazoparib (BMN 673), 2X- 15 121, CEP-9722, KU-0059436 (AZD2281), PF-01367338, AZD5305, AZD9574, seneparib (IMP4297), fluzoparib (SHR-3162), XIN005104, NMS-293 or a combination thereof. The DNA-PK inhibitor may be AZD7648, nedisertib (M3814), M9831, or BAY-8400. The cell checkpoint kinase inhibitor may be, e.g., RP-6306, MK-1775 or AZD1775, AZD7762, LY2606368, PF-0477736, AZD0156, GDC-0575, ARRY-575, CCT245737, PNT-737 or a combination thereof. 20 DNA-dependent Protein Kinase Inhibitors DNA-dependent Protein Kinase (DNA-PK) inhibitors that may be used in the present invention include compounds that upon contacting DNA-PK, whether in vitro, in cell culture, or in an animal, reduce the activity of DNA-PK, such that the measured DNA-PK IC50 is 10 µM or less (e.g., 5 µM or 25 less or 1 µM or less). For certain DNA-PK inhibitors, the DNA-PK IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the DNA-PK IC50 is 0.1 nM to 1 µM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Nonlimiting examples of DNA-PK inhibitors include AZD-7648, Peposertib, M9831, IMP11, NU5455, BAY-8400, ZL-2201, adMare Bioinnovations DNA-PK Program, XRD-0394, Avadomide,30 NERx Ku program, CC-115, KU57788, ZSTK474, LY3023414, BR101801, NK-314, NU7441, NU- 7026, VX-984, BAY-8400, KU-0060648, and pharmaceutically acceptable salts thereof. Examples of DNA-PK inhibitors: XRD-0394 248 PATENT ATTORNEY DOCKET: 51246-065WO2 ZL-2201 LY3023414 BY-8400 KU-006048 Antibody Drug Conjugates Antibody drug conjugates (ADCs) that may be used in the present invention include conjugates that upon contacting cancer cells, whether in vitro, in cell culture, or in an animal, inhibit 5 the cancer cell, such that the measured IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain ADCs, the IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the ADC IC50is 0.1 nM to 1 µM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). ADCs include Disitamab vedotin, Belantamab mafodotin, Trastuzumab deruxtecan, Ujvira, 10 Mirvetuximab soravtansine, Gemtuzumab ozogamicin, Enfortumab vedotin, Inotuzumab ozogamicin, Trastuzumab emtansine, Tisotumab vedotin, Sacituzumab govitecan, Polatuzumab vedotin, Loncastuximab Tesirine, Brentuximab vedotin, PF-06804103, MGTA-117, FOR46, MRG001, SOT102, ZV0203, AOC 1020, PRO1184, BAT8009, BB-1705, JS107, SHR-A1912, CMG901, Ladiratuzumab vedotin, BAT8006, RC108, BAT8008, Mipasetamab Uzoptirine, NBE-002, 249 PATENT ATTORNEY DOCKET: 51246-065WO2 Zanidatamab zovodotin, F0002-ADC, SKB315, GQ1001, ABBV-637, XMT-2056, TORL-1-23, FDA022, DYNE-251, STI-6129, Ozuriftamab vedotin, Farletuzumab Ecteribulin, Trastuzumab vedotin, DB-1303, OMTX705, TRS005, Ispectamab debotansine, DXC-005, ESG-401, ARX788, BAT8010, Tusamitamab ravtansine, ABBV-154, Naratuximab emtansine, PSMA ADC, TAK-164, ADCT-602, 5 ADCT-901, SHR-A1201, GB251, ABL202, SHR-A1921, 9MW2821, HS-20093, BIO-106, SKB264, Camidanlumab Tesirine, Datopotamab deruxtecan, Telisotuzumab vedotin, L-DOS47, AVID100, OBI- 999, DP303c, AURIXIM, MT-8633, IMGC936, BB-1701, AOC 1001, JS108, TAC-001, SYSA1801, SHR-A2009, TORL-2-307-ADC, BL-M07D1, STRO-001, A166, Mecbotamab vedotin, Trastuzumab duocarmazine, ASN004, ABBV-011, Mirzotamab clezutoclax, OBT076, HS630, SGN-STNV, FDA018,10 ABBV-400, AZD8205, IBI-343, SGN-ALPV, TAK-500, JBH492, ALT-P7, Ifinatamab deruxtecan, DXC- 004, IMGN151, XMT-1660, M1231, LM-102, ORM-5029, STI-3258, SGN-B7H4V, TPX-4589, IKS03, Zilovertamab Vedotin, ARX517, Pivekimab Sunirine, Lonigutamab Ugodotin, TRPH-222, MRG004a, DS-6000a, REGN5093-M114, Trastuzumab imbotolimod, RC88, HTI-1066, BI-CON-02, SGN- CD228A, AOC 1044, DB-1305, ABBV-319, Patritumab Deruxtecan, RC118, Trastuzumab rezetecan, 15 ARX305, Upifitamab Rilsodotin, NBT828, TAA013, BL-B01D1, BL-M02D1, GQ1007, DS-9606a, NBT508, B003, DX126-262, XB002, FS-1502, Praluzatamab ravtansine, AMT-151, M9140, Indatuximab ravtansine, Cofetuzumab pelidotin, RG7861, AGS62P1, CX-2029, SGN-B6A, Unspecified TROP2 ADC, Unspecified HER2 ADC, RC98 ADC, DYNE-101, SHR-A1904, Anetumab ravtansine, Vobramitamab duocarmazine, Luveltamab tazevibulin, Serclutamab talirine, MRG003,20 SYD1875, BYON3521, SGN-PDL1V, JSKN-003, YL201, HS-20089, DXC-007, SYS6002, and HDP- 101. Radiotherapy Radiotherapy may be used in conjunction with the other methods of this disclosure for the 25 treatment of cancer. Radiotherapy is a treatment method where ionizing radiation is provided to cancerous tissue to induce DNA damage and cell death. Radiotherapy methods of this disclosure include radiation from an external beam (i.e., external beam radiation), sealed source radiotherapy, (i.e., brachytherapy), and injection of radionuclide isotopes (i.e., radionuclide therapy) or radioligand therapy (RLT) in which pharmaceuticals including antibodies or cell surface ligands are linked to 30 radionuclides for administration. External beam radiation can include treatment with photons (X-rays), electrons, protons, carbon ions, and boron capture neutrons. Radionuclides used in brachytherapy, radionuclide therapy, and radioligand therapy can include, e.g.,:131I,177Lu,153Sm,90Y,223Ra,225Ac, 211At,213Bi,212Pb / 212Bi,161Tb,125I,131Cs,106Ru,103Pd,32P,33P,67Cu,89Sr,165Dy,166Ho,186Re,188Re, or 60Co. 35 In some embodiments, the radiotherapy is part of a chemoradiotherapy (CRT). The chemotherapeutic agent can be etoposide, doxorubicin, topotecan, irinotecan, fluorouracil, gemcitabine, paclitaxel, a platin, an anthracycline, and a combination thereof. The radiotherapy can be a treatment given with electrons, photons, protons, alpha-emitters, beta-emitters, other ions, radio-nucleotides, boron capture neutrons, and combinations thereof. 250 PATENT ATTORNEY DOCKET: 51246-065WO2 In some embodiments, the radiotherapy is given either with fractionation (e.g., 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, 1.85, 1.90, 1.95, and 2.00 Gy per day for 5 days a week) up to a total dose of 50-70 Gy. In some embodiments, the 5 radiotherapy is given either with fractionation (0.1 to 2 Gy per day for 5 days a week) up to a total dose of 50-70 Gy. Other fractionation schedules could also be envisioned, for example, a lower dose per fraction but given twice daily. Higher daily doses over a shorter period of time can also be given. In one embodiment, stereotactic radiotherapy as well as the gamma knife are used. In the palliative setting, other fractionation schedules are also widely used for example 25 Gy in 5 fractions or 30 Gy 10 in 10 fractions. For radiotherapy, the duration of treatment will be the time frame when radiotherapy is given. These interventions apply to treatment given with electrons, photons and protons, alfa-emitters or other ions, treatment with radio-nucleotides, for example, treatment with131I given to patients with thyroid cancer, as well in patients treated with boron capture neutron therapy. 15 Radiotherapy Ligands Radiotherapy Ligands (RLTs) that may be used in the present invention include agents that upon contacting cancer cells, whether in vitro, in cell culture, or in an animal, inhibit the cancer cell, such that the measured IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain RLTs, the IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM 20 or 10 pM. Preferably, the RLT IC50 is 0.1 nM to 1 µM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). RLTs include Zevalin, Actimab-A, Iomab-ACT, Iomab-B, Lutetium-177-DOTAGA-PEG-IAC, Tozaride, SS0110, BAY-2701439, 177Lu-rhPSMA-10.1, CTT-1403, Iopofosine, SAR-BBN, SAR- bisPSMA, SARTATE, FAP-2286, CONV-01-α,177Lu-PSMA-I&T, FPI-2059, FPI-1434, FPI-1966, 25 [177Lu] ludotadipep,161Tb-PSMA-I&T, ITM-31, ITM-11, JNJ-69086420, I-131-1095, Azedra, PSMA TTC / BAY-2315497,177Lu-DOTA-EB-TATE, Betalutin, AAA817, AAA603, Lutathera, Pluvicto, PPMX- T002, 186RNL, PNT2003, CAM-H2, AlphaMedix, RYZ101, Sn-117m-DTPA, TLX592, TLX66, TLX250, TLX591, TLX101,124I-omburtamab, GD2-SADA, and131I-omburtamab. 30 Immune Checkpoint Inhibitors Immune checkpoint inhibitors reinvigorate antitumor immune responses by interrupting co- inhibitory signaling pathways and promote immune-mediated elimination of tumor cells which can involve DNA damage or recognition of DNA damage. Immune checkpoint inhibitors that may be used in the present invention include compounds that upon contacting a cell, whether in vitro, in cell 35 culture, in an animal, or in a patient, block an immune checkpoint. Immune checkpoint inhibitors include: anti CTLA-4 Ipilimumab (Yervoy), anti PD-1 Nivolumab (Opdivo), anti PD-1 Pembrolizumab (KEYTRUDA), anti PD-1 Cemiplimab (LIBTAYO), anti PD-L1 Atezolizumab (TECENTRIQ), anti PD-L1 Avelumab (BAVENCIO), and anti PD-L1 Durvalumab (IMFINZI). Methods of the invention include the measurement of the pharmacodynamic activity of a 40 combination of two or more treatment agents, wherein a cell is contacted with the treatment agents 251 PATENT ATTORNEY DOCKET: 51246-065WO2 simultaneously. For example, the treatment agents may be combined in a pharmaceutical composition (e.g., as a mixture), and the cell is contacted with the pharmaceutical composition. Methods of the invention also include the measurement of the pharmacodynamic activity of a combination of two or more treatment agents, wherein a cell is contacted with the treatment agents 5 are administered sequentially. For example, a cell may be contacted with a first treatment agent, then contacted with the second treatment agent after a duration. In embodiments wherein the combination therapy includes three or more treatment agents, a cell may be contacted with any two or more treatment agents simultaneously or sequentially. For example, a cell may be contacted with a first treatment agent, then contacted with a pharmaceutical composition including a second treatment 10 agent and a third treatment agent. Methods of Measuring Pharmacodynamic Activity or Treatment Efficacy The disclosure provides methods for measuring the pharmacodynamic activity of a Polθ inhibitor or a PARP inhibitor, or the efficacy of a treatment for a disease, condition, or disorder (e.g., 15 cancer). The invention is built on the discovery that unrepaired DNA errors resulting from TMEJ and MMEJ increase the accumulation of CIP2A foci. By measuring CIP2A foci accumulation (e.g., measuring the CIP2A foci per mitotic event), the pharmacodynamic activity of a Polθ inhibitor or a PARP inhibitor may then be measured. Methods of the invention include contacting a cell with a Polθ inhibitor or a PARP inhibitor, 20 measuring an experimental signal intensity; and comparing the experimental signal intensity with a reference signal intensity. In some embodiments, the signal intensity is proportional to the CIP2A foci accumulation in the cell. In some embodiments, the signal intensity is proportional to the CIP2A foci accumulation per mitotic event in the cell. In some embodiments, the experimental signal intensity is proportional to the CIP2A foci accumulation per mitotic event in a cell contacted with the Polθ inhibitor 25 or the PARP inhibitor. In some embodiments, the reference signal intensity is the CIP2A foci accumulation per mitotic event in a healthy cell (e.g., a wild-type cell, e.g., a non-cancer cell). In some embodiments, the reference signal intensity is the CIP2A foci accumulation in a second cell not contacted with an inhibitor (e.g., a cancer cell not contacted with the Polθ inhibitor or the PARP inhibitor). In some 30 embodiments, the reference signal intensity is obtained from the independent measurement of the CIP2A foci per mitotic event in a second cell contacted with a Polθ inhibitor or a PARP inhibitor different from the Polθ inhibitor or the PARP inhibitor the first cell was contacted with. In some embodiments, the reference signal intensity and the experimental signal intensity are obtained in a paired biopsy. For example a cell biopsy including an reference cell may be taken from 35 a subject. The reference signal intensity may then be obtained using the reference cell. The subject may then be administered an inhibitor (e.g., a Polθ inhibitor or a PARP inhibitor) on a dosing schedule for a duration of treatment. After a duration of treatment, an experimental cell biopsy including an experimental cell may be taken from the subject. The experimental signal intensity may then be obtained using the experimental cell. The experimental signal intensity may then be compared to the 40 reference signal intensity to determine the efficacy of the treatment on the subject. 252 PATENT ATTORNEY DOCKET: 51246-065WO2 Based on the results of the method, the dose of the inhibitor the subject is administered may be altered (e.g., the subject may be administered an increased dose of the inhibitor or a decreased dose of the inhibitor) or the inhibitor the subject is treated with may be changed. For example, a subject being treated exclusively with a Polθ inhibitor may have the dose of the Polθ inhibitor 5 increased or decreased. Additionally, the subject may begin a dosing regimen including a Polθ inhibitor and a second treatment agent. As a further example, a subject being treated with a combination therapy may have the dose of one or more treatments in the combination therapy altered, or one treatment agent of the combination therapy may be changed for a different treatment agent, or removed from the combination therapy. The efficacy of this altered treatment may then be 10 evaluated, e.g., by obtaining an experimental signal intensity from a cell obtained from the subject after being treated with the altered treatment and comparing the experimental signal intensity to a reference signal intensity (e.g., the reference signal intensity obtained before the subject was administered any treatment or the experimental signal intensity from the subject prior treatment regimen). 15 In some embodiments, the treatment duration is at least 1 day (e.g., at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 20 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, at least 50 days, at least 55 days, or at least 60 days). In some embodiments, the duration is from 1 20 day to 60 days. In some embodiments, the inhibitor may be continuously administered (e.g., on a dosing schedule) for the treatment duration. In some embodiments, the experimental signal intensity and the reference signal intensity are each a fluorescence signal intensity. In some embodiments, the fluorescence signal intensity is obtained from, e.g., fluorescence polarization (FP), fluorescent intensity (FI), or time-resolved Förester 25 resonance energy transfer (TR-FRET). In some embodiments, the signal intensity may be measured by fluorescence microscopy, confocal fluorescence microscopy, or bright field microscopy. In some embodiments, the measurement of a signal intensity may include an immunostaining step. In some embodiments, the immunostaining is immunofluorescence or immunochemistry. Exemplary methods of immunostaining are known in the art, see, e.g., U.S. Patent No.10,551,386, the methods of 30 immunostaining of which are incorporated herein by reference. In some embodiments, the reference signal intensity may be an average signal intensity from a plurality of cells. In some embodiments, the experimental signal intensity from a plurality of cells may be measured, and the average value of the experimental signal intensity from the plurality of cells may be compared to the reference signal intensity. 35 In some embodiments, the experimental signal intensity and the reference signal intensity are proportional to the accumulation of CIP2A foci. In some embodiments, the reference signal intensity correlates to from about 1% of mitotic events to about 10% of mitotic events having a CIP2A foci accumulation of at least a threshold value (e.g., about 1% of mitotic events, about 2% of mitotic events, about 3% of mitotic events, about 4% of mitotic events, about 5% of mitotic events, about 6% 253 PATENT ATTORNEY DOCKET: 51246-065WO2 of mitotic events, about 7% of mitotic events, about 8% of mitotic events, about 9% of mitotic events, or about 10% of mitotic events have a CIP2A foci accumulation greater than the threshold value.). In some embodiments, the Polθ inhibitor or the PARP inhibitor are identified as effective when at least 1% of mitotic events are determined to have a CIP2A foci accumulation per mitotic event at 5 least a threshold value (e.g., at least 1% of mitotic events, at least 2% of mitotic events, at least 3% of mitotic events, at least 4% of mitotic events, at least 5% of mitotic events, at least 6% of mitotic events, at least 7% of mitotic events, at least 8% of mitotic events, at least 9% of mitotic events, at least 10% of mitotic events, at least 11% of mitotic events, at least 12% of mitotic events, at least 13% of mitotic events, at least 14% of mitotic events, at least 15% of mitotic events, at least 16% of mitotic 10 events, at least 17% of mitotic events, at least 18% of mitotic events, at least 19% of mitotic events, at least 20% of mitotic events, at least 21% of mitotic events, at least 22% of mitotic events, at least 23% of mitotic events, at least 24% of mitotic events, at least 25% of mitotic events, at least 26% of mitotic events, at least 27% of mitotic events, at least 28% of mitotic events, at least 29% of mitotic events, at least 30% of mitotic events, at least 35% of mitotic events, at least 40% of mitotic events, at least 45% 15 of mitotic events, or at least 50% of mitotic events are determined to have a CIP2A foci accumulation per mitotic event greater than the threshold value). In some embodiments, the threshold value of CIP2A foci accumulation is at least 5 (e.g., at least 6, at least 7, at least 8, at least 9, or at least 10). In some embodiments, the threshold value of CIP2A foci accumulation is determined for an individual subject. In some embodiments, the threshold 20 value of CIP2A foci accumulation is determined for an individual Polθ inhibitor or an individual PARP inhibitor. In some embodiments, the threshold value for CIP2A foci accumulation is determined for an individual combination therapy. In some embodiments, the cell is a preserved cell. In some embodiments, the cell is preserved in formalin-fixed paraffin-embedded (FFPE) tissue. Other exemplary methods of preserving 25 cells include those in, e.g., International Patent Publication Nos. WO 2015 / 111686; WO 2018 / 064975; WO 2018 / 087558; WO 2004 / 058323; and WO 2023 / 274338; the devices, systems, and compositions for cell preservation are incorporated herein by reference. In some embodiments, the cell is obtained from a cell biopsy of a subject. In some embodiments, the cell biopsy is of a tumor, and the cell is a cancer cell. 30 In some embodiments, the Polθ inhibitor may be, e.g., a compound described herein (e.g., a compound selected from Table 1 or Table 2). In some embodiments, the PARP inhibitor may be, e.g., a compound herein (e.g., a compound selected from Table 3). In some embodiments, the Polθ inhibitor or the PARP inhibitor may be a compound of known activity, and the methods may be directed to determining the efficacy of treating a subject with the Polθ inhibitor or the PARP inhibitor. 35 In some embodiments, the PARP inhibitor or the Polθ may be a compound whose activity is not known prior to the method. Kits The disclosure provides kits with one or more elements which enable an artisan to perform an 40 assay including a method described herein. For example, a kit which enables an artisan to evaluate 254 PATENT ATTORNEY DOCKET: 51246-065WO2 the pharmacodynamic activity of a Polθ inhibitor or a PARP inhibitor may include, e.g., (a) a cell (e.g., a cancer cell, e.g., a tumor cell); (b) an assay buffer; (c) a multi-well plate; and (d) a stain. Alternatively, a kit which enables an artisan to determine the efficacy of a treatment of a disease, condition, or disorder (e.g., cancer) with a Polθ inhibitor or a PARP inhibitor may include, e.g., (a) the 5 Polθ inhibitor or the PARP inhibitor; (b) an assay buffer; (c) a multi-well plate; and (d) a stain. A kit of the invention may include a cell (e.g., a preserved cell). A kit including a preserved cell may be used in an assay to determine the pharmacodynamic activity of a Polθ inhibitor or a PARP inhibitor. Alternatively, a kit of the invention may include a Polθ inhibitor or a PARP inhibitor with a previously determined pharmacodynamic activity. kit including a Polθ inhibitor or a PARP inhibitor with 10 known pharmacodynamic activity may be used in an assay in combination with a cell (e.g., a cancer cell) obtained from a subject (e.g., by a cell biopsy) to determine the efficacy of a Polθ inhibitor or a PARP inhibitor in treating a disease, condition, or disorder of the subject (e.g., cancer). In some embodiments, the Polθ inhibitor may be, e.g., a compound described herein (e.g., a compound selected from Table 1 or Table 2). In some embodiments, the PARP inhibitor may be, e.g., 15 a compound herein (e.g., a compound selected from Table 3). In some embodiments, the Polθ inhibitor or the PARP inhibitor may be a compound of known activity, and the methods may be directed to determining the efficacy of treating a subject with the Polθ inhibitor or the PARP inhibitor. The kit may then enable an artisan to evaluate the efficacy of treatment of a subject with the Polθ inhibitor or the PARP inhibitor. In some embodiments, the PARP inhibitor or the Polθ may be a 20 compound whose activity is not known prior to the method. The kit may then enable an artisan to determine the pharmacodynamic activity of a Polθ inhibitor or a PARP inhibitor. A kit of the invention includes a stain which enables the measuring of CIP2A foci in a subject. A stain includes any materials which enable CIP2A foci accumulation to be measured by an artisan. In some embodiments, measurement is done by immunostaining (e.g., immunofluorescence or 25 immunochemistry). In some embodiments, the stain includes an antibody specific to CIP2A (e.g., DNA topoisomerase 2-binding protein 1 (TOPBP1), mediator of DNA damage checkpoint 1 (MDC1), or combinations thereof). In some embodiments, a kit may further include a detector for measuring a signal provided by the stain. For example, a kit may include a photodetector for measuring the light fluoresced by the stain. 30 In some embodiments, the cell is a preserved cell. In some embodiments, the cell is preserved in formalin-fixed paraffin-embedded (FFPE) tissue. Other exemplary methods of preserving cells include those in, e.g., International Patent Publication No. WO 2015 / 111686; WO 2018 / 064975; WO 2018 / 087558; WO 2004 / 058323; and WO 2023274338; the devices, systems, and compositions for cell preservation are incorporated herein by reference. In some embodiments, the cell is obtained 35 from a cell biopsy of a subject. In some embodiments, the cell biopsy is of a tumor, and the cell is a cancer cell. Methods of Treatment A compound evaluated by the methods of the invention may be used in the treatment of a 40 disease or condition. The disease or condition may have the symptom of cell hyperproliferation. For 255 PATENT ATTORNEY DOCKET: 51246-065WO2 example, the disease or condition may be a cancer. The cancer may be, e.g., carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, or melanoma. Non-limiting examples of cancers include prostate cancer, breast cancer, ovarian cancer, multiple myeloma, brain cancer, glioma, lung cancer, salivary cancer, stomach cancer, thymic 5 epithelial cancer, thyroid cancer, leukemia, melanoma, lymphoma, gastric cancer, pancreatic cancer, kidney cancer, bladder cancer, colon cancer, and liver cancer. Non-limiting examples of carcinomas include medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell 10 carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, 15 encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, 20 intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, 25 nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, 30 carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum. Non-limiting examples of sarcomas include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy’s sarcoma, adipose sarcoma, liposarcoma, 35 alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, 256 PATENT ATTORNEY DOCKET: 51246-065WO2 angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma. Non-limiting examples of leukemias include acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute 5 promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphoma, lymphatic leukemia, lymphoblastic leukemia, lymphocytic 10 leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and 15 undifferentiated cell leukemia. Non-limiting examples of melanomas include acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma. 20 A compound evaluated by the methods of the invention may be administered by a route selected from the group consisting of oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, intratumoral, and topical administration. The methods of the invention may include a step of identifying a subject as being a candidate 25 for a Polθ inhibitor therapy. For example, the subject may be identified as being a candidate for a Polθ inhibitor therapy by determining (i) whether the subject has cancer with defects in DNA repair; (ii) whether the subject has cancer, cancer cells, or cells expressing genetic aberrations in cancer-driving genes or oncogenes; (iii) whether the subject has cancer, cancer cell, or cells with one or more defect(s) in a protein or gene involved in DNA repair; (iv) whether the subject has cancer with defects 30 in a protein or gene involved in homologous recombination; (v) whether the subject has a cancer with defects in a protein or gene that have been implicated in sensitivity to Polθ inhibitors or genetic perturbation of Polθ; or (vi) whether the subject has a cancer with genetic or protein characteristics that have been implicated in sensitivity to Polθ inhibitors. The compounds, compositions, and methods described may be used to treat a subject having 35 a cancer with an aberration in DNA repair. For example, the aberration in DNA repair may be, e.g., altered expression or activity of one or more of the following proteins / genes including but not limited to: BRCA2 and BRCA1. Aberrations in DNA repair may be identified by the presence of genomic scars reflective of use of microhomologies in DNA repair. Additionally, DNA repair may be identified as follows: 20% or greater change in RAD51 or gamma-H2AX foci. 257 PATENT ATTORNEY DOCKET: 51246-065WO2 The compounds, compositions, and methods described may be used to treat a subject having a cancer, cancer cells, or cells with one or more aberration(s) in DNA repair. For example, cancers which are homologous repair deficient by mechanisms other than BRCA deficiency, such as those with promoter hypermethylation. In these tumours where no DSB repair pathway may be fully down 5 regulated the Polθ inhibitor may be given along with another DNA damage response modulator such as a PARP inhibitor (e.g., as described herein above), a DNA-PK inhibitor (as described herein above), an ATM inhibitor, an ATR inhibitor, a Wee1 inhibitor, a PKMYT1 inhibitor, or a CHK1 inhibitor. Nonlimiting examples of ATM inhibitors include the compounds M3541, M4076 (lartesertib), AZD0156, KU-55933, and wortmannin, and pharmaceutically acceptable salts thereof. 10 Examples of ATM inhibitors: wortmannin The term “ATR inhibitor,” as used herein, refers a compound that upon contacting the enzyme Atr kinase, whether in vitro, in cell culture, or in an animal, reduces the activity of Atr kinase, such that the measured Atr kinase IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Atr 15 inhibitors, the Atr kinase IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the Atr kinase IC50 is 0.1 nM to 1 µM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Non-limiting examples of ATR inhibitors include, e.g., the compounds camonsertib, elimusertib, ceralasertib, berzonsertib, gartisertib, tuvusertib, SKLB-197, and pharmaceutically acceptable salts thereof, as well as the compounds disclosed in U.S. Patent 20 Nos.12,264,155, 11,028,076, 10,800,781, 10,093,676, 10,745,420, 10,301,324, 10,196,405, 9,663,535, 9,549,932, 8,552,004, and 8,841,308, U.S. Patent Application Publication Nos.: 258 PATENT ATTORNEY DOCKET: 51246-065WO2 2022 / 0185809, 2019 / 0055240, and 2019 / 0300547, and International Application Publication Nos. WO 2020087170, WO 2018218197, WO 2020259601, WO 2019036641, WO 2020049017, WO2019154365, WO 2020103897, WO2021233376, WO2022028598, WO2022012484, WO2022002245, WO2022002243, and pharmaceutically acceptable salt of the disclosed compounds, 5 each of these references is incorporated by reference herein. Examples of ATR inhibitors: ceralasertib (AZD6738) The term, “Wee1 inhibitor,” as used herein, refers to a compound that, upon contacting Wee1, whether in vitro, in cell culture, or in an animal, reduce the activity of Wee1, such that the measured 10 Wee1 IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Wee1 inhibitors, Wee1 IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 259 PATENT ATTORNEY DOCKET: 51246-065WO2 10 pM. Preferably, Wee1 IC50 is 0.1 nM to 1 µM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Non-limiting examples of Wee1 inhibitors include, e.g., the compounds AZD1775, MK- 1775, Debio-0123, and ZN-c3, and pharmaceutically acceptable salts thereof, and compounds disclosed in US Patent Nos.: 8,710,065; 8,716,297; 8,791,125, 9,181,239; 9,850,247; 11,332,473; 5 11,345,711; 11,208,413; 11,248,006; 11,613,545; and 11,261,192; US Patent Application No. 17 / 441,085; and International Patent Publication Nos.: WO 2013012681; WO 2018090939; WO 2018171633; WO 2019028008; WO 2019085933; WO 2019173082; WO 2020192581; WO 2020210320; WO 2020210377; WO 2021073491; WO 2021207598; WO 2022155202; WO 2022188802; WO 2022251224; and WO 2022256680; the Wee1 inhibitors of which, and 10 pharmaceutically acceptable salts thereof, are all incorporated herein by reference in their entirety. Example Wee1 inhibitors: Adavosterib Azenosterib WO2020192581 Example 59 The term “PKMyt1 inhibitor,” as used herein, refers to a compound that, upon contacting the enzyme Myt1, whether in vitro, in cell culture, or in an animal, reduces the activity of Myt1, such that 15 the measured Myt1 IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). Nonlimiting examples of PKMyt1 inhibitors include lunresertib (RP-6306), and pharmaceutically acceptable salts thereof, and the compounds disclosed in US 2023 / 0151014, which is incorporated by reference herein, and pharmaceutically acceptable salts thereof. 260 PATENT ATTORNEY DOCKET: 51246-065WO2 (lunresertib) The term, “Chek1 inhibitor,” as used herein, refers to a compound that, upon contacting Chek1, whether in vitro, in cell culture, or in an animal, reduce the activity of Chek1, such that the measured Chek1 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Chek1 5 inhibitors, Chek1 IC50 may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, Chek1 IC50 is 0.1 nM to 1 µM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Nonlimiting examples of Chek1 inhibitors include the compound SRA737 (CAS No.: 1489389-18-5), and pharmaceutically acceptable salts thereof, as well as compounds disclosed in US 7,067,506; US 8,093,244; US 8,410,279; US 8,530,468; US 8,618,121; 10 US 8,916,591; US 9,067,920; US 9,440,976; US 10,189,818; US 10,822,327; US 20090182001; US 20090233896; US 20090258852; US20090270416; US 20090275570; US 20150368244; US 20180369202; and US 20200397796; the Chek1 inhibitors disclosed therein and pharmaceutically acceptable salts thereof, are incorporated herein by reference in their entirety. 15 The compounds, compositions, and methods described may be used to treat a subject having a cancer, cancer cells or cells with one or more aberration(s) in a protein or gene involved in homologous recombination. For example, the aberration in homologous recombination may be altered expression or activity of one or more of the following proteins / genes including but not limited to: BRCA1, BRCA2, MRE11, RAD50, RAD51, RAD52, RAD54L, NBN, ATM, H2AX, PALB2, RPA, 20 BRIP1, BARD1, ATR, ATRX, CHK1, CDK12, CHK2, MDM2, MDM4, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, and FANCL. The compounds, compositions, and methods described may be used to treat a subject having a cancer, cancer cells or cells with one or more aberration(s) in a protein or gene implicated in sensitivity to Polθ inhibitors or genetic perturbation of the Polθ signaling pathway including Polθ over- 25 expression. There are many methods known in the art for determining whether a tumor has an aberration in a protein or gene. For example, sequencing of either the genomic DNA or mRNA products of each specified gene (e.g., UNG, PARP1, or LIG1) can be performed on a sample of the tumor to establish whether mutations expected to modulate the function or expression of the gene product are present. 30 In addition to the mutational inactivation, tumor cells can modulate a gene by hypermethylating its 261 PATENT ATTORNEY DOCKET: 51246-065WO2 promoter region, leading to reduced gene expression. This is most commonly assessed using methylation-specific polymerase chain reaction (PCR) to quantify methylation levels on the promoters of base excision repair genes of interest. Analysis of DNA repair gene promoter methylation is available commercially. 5 The expression levels of genes can be assessed by directly quantifying levels of the mRNA and protein products of each gene using standard techniques, e.g., quantitative reverse transcriptase- coupled polymerase chain reaction (RT-PCR), RNA-Seq for gene expression, and immunohistochemistry (IHC) for protein expression. Gene amplification or deletion leading to aberrantly over- or under- expressed proteins (respectively) can also be measured by FISH 10 (fluorescent in situ hybridization) analysis using a probe specific for the gene of interest. The methods described above (gene sequence, promoter methylation, and mRNA expression) may also be used to characterize the status (e.g., expression or mutation) of other genes or proteins of interest, e.g., DNA-damaging oncogenes expressed by a tumor or defects in the DNA repair pathways of a cell. 15 Formulations A compound identified as capable of treating any of the conditions described herein by any of the methods described herein, may be administered to patients or animals with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form. The chemical compounds for use in such 20 therapies may be produced and isolated by any standard technique known to those in the field of medicinal chemistry. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the identified compound to patients suffering from a bacterial infection. Administration may begin before the patient is symptomatic. Exemplary routes of administration of the compounds (e.g., a compound evaluated by the 25 methods of the invention), or pharmaceutical compositions thereof, used in the present invention include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. The compounds desirably are administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of the compounds described herein 30 formulated for treatment of the disorders described herein are also part of the present invention. Formulations for Oral Administration The pharmaceutical compositions contemplated by the invention include those formulated for oral administration (“oral dosage forms”). Oral dosage forms can be, for example, in the form of 35 tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating 40 agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato 262 PATENT ATTORNEY DOCKET: 51246-065WO2 starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and 5 lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like. Stabilized amorphous formulations may also be used for oral administration. A technique such as spray-dried dispersion may be used in which the active drug is mixed with a polymer such as 10 a cellulose derivative (e.g., cellulose acetate phthalate (CAP), methylcellulose acetate phthalate, hydroxypropylmethyl cellulose (HPMC), and hydroxypropylmethyl cellulose acetate succinate (HPMCAS, e.g., HPMCAS grade H, HPMCAS grade L, and HPMCAS grade M)), a polyacrylate (e.g., polymethacrylate, a methacrylate copolymer, and an ethacrylate copolymer), a polyvinyl pyrrolidone, a polyvinyl acetate (e.g., polyvinyl acetate ester and a polyethylene glycol-polyvinylcaprolactam- 15 polyvinylacetate copolymer), or a copolymer of a polyvinyl pyrrolidone and a polyvinyl acetate, and combinations thereof dissolved in an organic solvent. The resulting solution may be rapidly dried by a stream of air in a spray drying apparatus to produce a fine powder containing the active drug as an amorphous solid. Alternatively, the active drug may be dissolved in a polymer carrier such as povidone, hydroxypropyl methylcellulose, microcrystalline cellulose, or a mixture of such agents, 20 using a hot melt extrusion process to generate an amorphous solid. Formulations for oral administration may also be presented as chewable tablets, as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, 25 liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment. Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and / or the diffusion of the active drug substance. Any of a number of 30 strategies can be pursued in order to obtain controlled release and the targeted plasma concentration versus time profile. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and35 liposomes. In certain embodiments, compositions include biodegradable, pH, and / or temperature- sensitive polymer coatings. Dissolution or diffusion-controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances 40 mentioned above and / or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl 263 PATENT ATTORNEY DOCKET: 51246-065WO2 alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3-butylene glycol, ethylene glycol methacrylate, and / or polyethylene 5 glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbon. The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or 10 oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. An oral dosage form may include a compound of formula (I) or a compound of formula (PI). In some embodiments, the compound of the pharmaceutical composition may be a prodrug of an active compound. For example, the prodrug may be a compound of formula (PI) which is converted after 15 administration to an active compound of formula (I). The pharmaceutical composition may be formulated to favor conversion of the prodrug to the active compound after administration to a subject. In some embodiments, one or more steps of the conversion are performed by one or more enzymes endogenous to a subject. In some embodiments, the one or more enzymes include an enzyme which removes or converts phosphoryl groups on a molecule (e.g., a phosphatase) or an enzyme which 20 removes or converts ester groups on a molecule (e.g., an esterase). Formulations for Parenteral Administration The compounds described herein for use in the methods of the invention can be administered in a pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulation as 25 described herein. The pharmaceutical formulation may also be administered parenterally (intravenous, intramuscular, subcutaneous or the like) in dosage forms or formulations containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation 30 isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. For example, to prepare such a composition, the compounds of the invention may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium 35 hydroxide or a suitable buffer, 1,3-butanediol, Ringer’s solution and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, for example, methyl, ethyl, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), herein incorporated by reference. 264 PATENT ATTORNEY DOCKET: 51246-065WO2 The parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration: (1) “Drug Injection:” a liquid preparation that is a drug substance (e.g., a compound evaluated by the methods of the invention), or a solution thereof; 5 (2) “Drug for Injection:” the drug substance (e.g., a compound evaluated by the methods of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection; (3) “Drug Injectable Emulsion:” a liquid preparation of the drug substance (e.g., a compound evaluated by the methods of the invention) that is dissolved or dispersed in a suitable emulsion 10 medium; (4) “Drug Injectable Suspension:” a liquid preparation of the drug substance (e.g., a compound evaluated by the methods of the invention) suspended in a suitable liquid medium; and (5) “Drug for Injectable Suspension:” the drug substance (e.g., a compound evaluated by the methods of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for 15 parenteral administration as a drug injectable suspension. Formulations for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, e.g., hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to 20 prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013. Formulations for parenteral administration may, for example, contain excipients, sterile water, 25 or saline, polyalkylene glycols, e.g., polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for 30 inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. The parenteral formulation can be formulated for prompt release or for sustained / extended release of the compound. Exemplary formulations for parenteral release of the compound include: 35 aqueous solutions, powders for reconstitution, cosolvent solutions, oil / water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymeric gels. Examples The following examples were meant to illustrate the invention. They were not meant to limit 40 the invention in any way. 265 PATENT ATTORNEY DOCKET: 51246-065WO2 Example 1: Elevation of Mitotic CIP2A focus formation with Polθ Inhibitors To demonstrate that Polθ inhibition elevates CIP2A focus accumulation on mitotic chromosomes in tumor cells, HCT116 and DLD1 wild-type (WT) or isogenic BRCA2-deficient 5 (BRCA2-KO) colorectal carcinoma cells were treated with exemplary Polθ inhibitor, compound 431, for 4 days. CIP2A was visualized by immunofluorescence using a specific antibody DNA topoisomerase 2-binding protein 1 (TOPBP1). The number of CIP2A foci and the intensity of CIP2A nuclear signal were quantified in mitotic cells, marked by phospho-histone H3 (pH3-S10), with either automated high-throughput image analysis or manual quantification. A dose-dependent increase in 10 CIP2A focus number as well as CIP2A intensity was observed in both WT and BRCA2-KO cells of either background (HCT116 and DLD1; Figs.1A-1D). The increase in CIP2A foci was a direct consequence of inhibition of Polθ activity, as a comparable increase in CIP2A focus number was observed in DLD1 cells both after compound 431 treatment and a genetic inactivation of the POLQ gene in an isogenic cell line (POLQ-KO; Fig.1B). 15 Example 2: Elevation Of Mitotic CIP2A Focus Formation With Combination Treatments To investigate combination therapies using a Polθ inhibitor and a PARP inhibitor, CIP2A focus formation was evaluated in HCT116 BRCA2-KO cells treated with either compound 431, the PARP inhibitor AZD5305, or their combination for 24h. As shown in Fig.2A-2B, single-agent AZD5305 20 treatment elevated CIP2A focus formation in BRCA2-KO cells. At the same time, the combination of AZD5305 and compound 431 resulted in a further, synergistic, increase in mitotic cells with >10 CIP2A foci (Fig.2B). This data demonstrates that CIP2A focus number is also a readout of the pharmacodynamic activity of PARP inhibitors. Moreover, this data demonstrates that CIP2A is also a feasible readout of the pharmacodynamic activity of a combination therapy with a Polθ inhibitor and a 25 PARP inhibitor, and that the effects of combined Polθ and PARP inhibition on CIP2A can be distinguished from each single agent treatment. Example 3: In-Vivo Elevation of CIP2A Focus Formation with Polθ Inhibitors The effect of Polθ inhibition on CIP2A focus formation in vivo was tested with compound 431 30 both as a single-agent or in combination with a PARP inhibitor on HCT116 BRCA2-KO subcutaneous mouse xenografts. Immunodeficient mice carrying HCT116 BRCA2-KO tumors were dosed either with vehicle, compound 431 (60 mg / kg by oral gavage), olaparib (25 mg / kg), or a combination of compound 431 and olaparib for 4 days. The tumor tissue was subsequently harvested and processed for immunofluorescence using CIP2A and pH3-S10 specific antibodies (Fig.3A). An increase in 35 CIP2A foci formation was observed upon either single agent treatment, or the combination of compound 431 and olaparib after as early as 4 days of treatment (Fig.3B). Importantly, among the treatment arms the compound 431 and olaparib combination induced the largest increase in cells with more than 10 CIP2A foci, consistent with the profound anti-tumor activity of this combination observed in a multi-week efficacy study (Fig.3C). This data demonstrates that CIP2A is a feasible readout of 266 PATENT ATTORNEY DOCKET: 51246-065WO2 the pharmacodynamic activity of Polθ inhibitor therapies, PARP inhibitor therapies, and combination therapies with Polθ inhibitors and PARP inhibitors in vivo. Example 4: Evaluation of CIP2A Focus Formation after Polθ Inhibitor Treatment in Human 5 Tumor Biopsies To confirm that Polθ inhibitor treatment increases nuclear CIP2A accumulation in human tumors, samples from two paired biopsies of human BRCA1-mutated ovarian tumors, before (FIG.4A) and after (FIG.4B) Polθ inhibitor administration, were stained with anti-CIP2A and anti-H3pS10 (mitotic marker) antibodies and quantified. Notably, the Polθ inhibitor treatment increased the 10 percentage of CIP2A-positive cells as compared to pre-treatment controls in both tumors (FIG.5). Enumerated Embodiments E1. A method of evaluating the pharmacodynamic activity of an inhibitor selected from a Polθ inhibitor or a PARP inhibitor, comprising: 15 (a) contacting an experimental cell with the inhibitor; (b) measuring an experimental CIP2A signal intensity in the experimental cell; and (c) comparing the experimental CIP2A signal intensity to a reference CIP2A signal intensity; wherein the experimental CIP2A signal intensity is proportional to proportional to the accumulation of CIP2A foci in the experimental cell, and the pharmacodynamic activity of the inhibitor is proportional 20 to the difference between the experimental CIP2A signal intensity and the reference CIP2A signal intensity. E2. The method of embodiment E1, wherein the experimental cell is obtained from an experimental tissue biopsy on a subject prior to step (a). E3. The method of embodiment E2, wherein the tissue biopsy is a tumor biopsy and the 25 experimental cell is a tumor cell. E4. A method of measuring the efficacy of a treatment of a subject with an inhibitor selected from a Polθ inhibitor or a PARP inhibitor, the method comprising (a) obtaining an experimental tissue biopsy from the subject; (b) contacting an experimental cell from the experimental tissue biopsy the cell with the 30 inhibitor; (c) measuring an experimental CIP2A signal intensity in the experimental cell; and (d) comparing the experimental CIP2A signal intensity with a reference CIP2A signal intensity; wherein the treatment is more effective if the experimental signal intensity is greater than the reference signal intensity. 35 E5. The method of any one of embodiments E1 to E4, wherein the reference CIP2A signal intensity is measured in a reference cell. E6. The method of embodiment E5, wherein the reference cell is obtained from a reference tissue biopsy. E7. The method of embodiment E6, wherein the reference tissue biopsy is a tumor biopsy 40 and the reference cell is a tumor cell. 267 PATENT ATTORNEY DOCKET: 51246-065WO2 E8. The method of embodiment E5, wherein the reference cell is a wild type cell. E9. The method of embodiment 5, wherein the reference cell is obtained from the experimental tissue biopsy. E10. The method of any one of embodiments E5 to E9, wherein the reference cell is not 5 contacted with a Polθ inhibitor or a PARP inhibitor prior to measuring the reference signal intensity. E11. The method of any one of embodiments E5 to E10, wherein the reference signal intensity is proportional to the CIP2A foci per mitotic event in the reference cell when the reference cell is contacted with a different inhibitor than the experimental cell. E12. The method of any one of embodiments E5 to E11, wherein the reference signal 10 intensity is proportional to the CIP2A foci per mitotic event obtained with a Polθ inhibitor or a PARP inhibitor different from the experimental cell. E13. A method of measuring the efficacy of a treatment of a subject with an inhibitor selected from a Polθ inhibitor or a PARP inhibitor, the method comprising (a) obtaining a reference tissue biopsy from the subject, the reference tissue biopsy 15 comprising a reference cell; (b) measuring a reference CIP2A signal intensity from the reference cell; (c) administering the inhibitor to the subject; (d) allowing a duration of treatment to elapse; (e) obtaining an experimental tissue biopsy from the subject, the experimental tissue biopsy 20 comprising an experimental cell; (f) contacting the experimental cell with the inhibitor; (g) measuring an experimental CIP2A signal intensity in the experimental cell; and (h) comparing the experimental CIP2A signal intensity with a reference CIP2A signal intensity; wherein the treatment is more effective if the experimental CIP2A signal intensity is greater than the 25 reference CIP2A signal intensity. E14. The method of embodiment E13, wherein the duration of treatment is at least 1 day. E15. The method of embodiment E13, wherein the duration of treatment is at least 10 days. E16. The method of embodiment E13, wherein the duration of treatment is at least 20 days. E17. The method of embodiment E13, wherein the duration of treatment is at least 30 days. 30 E18. The method of embodiment E13, wherein the duration of treatment is at least 45 days. E19. The method of embodiment E13, wherein the duration of treatment is at least 60 days. E20. The method of any one of embodiments E13 to E19, wherein the inhibitor is administered continuously to the subject throughout the duration of treatment. E21. The method of any one of embodiments E13 to E19, wherein the inhibitor is 35 administered on a dosing schedule to the subject throughout the duration of treatment. E22. The method of any one of embodiments E13 to E21, wherein the reference tissue biopsy is a tumor biopsy and the reference cell is a tumor cell. E23. The method of any one of embodiments E13 to E22, wherein the reference cell is not contacted with a Polθ inhibitor or a PARP inhibitor prior to measuring the reference signal intensity. 268 PATENT ATTORNEY DOCKET: 51246-065WO2 E24. The method of any one of embodiments E2 to E23, wherein the experimental tissue biopsy is a tumor biopsy and the experimental cell is a tumor cell. E25. The method of any one of embodiments E2 to E24, wherein the subject is suffering from a disease or disorder. 5 E26. The method of embodiment E25, wherein the disease or disorder is cancer. E27. The method of embodiment E26, wherein the cancer is a carcinoma, sarcoma, adenocarcinoma, leukemia, lymphoma, or melanoma. E28. The method of embodiment E27, wherein the cancer is a carcinoma selected from the group consisting of medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar 10 carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus 15 carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, 20 hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, 25 mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, 30 carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum. 35 E29. The method of embodiment E27, wherein the cancer is a sarcoma selected from the group consisting of chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy’s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, 40 fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple 269 PATENT ATTORNEY DOCKET: 51246-065WO2 pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma. 5 E30. The method of embodiment E27, wherein the cancer is a leukemia selected from the group consisting of nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, 10 Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic 15 leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia. E31. The method of embodiment E27, wherein the cancer is a melanoma selected from the group consisting of acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, 20 Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma. E32. The method of embodiment E27, wherein the cancer is prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head & neck 25 cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterus cancer, medulloblastoma, colorectal cancer, or pancreatic cancer. E33. The method of embodiment E27, wherein the cancer is Hodgkin's disease, Non- Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian 30 cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, 35 colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer. E34. The method of any one of embodiments E1 to E33, wherein the experimental cell is preserved before contacting the cell with the inhibitor. E35. The method of embodiment E34, wherein the experimental cell is preserved with formalin-fixed paraffin embedded (FFPE) tissue. 270 PATENT ATTORNEY DOCKET: 51246-065WO2 E36. The method of any one of embodiments E5 to E35, wherein the reference cell is preserved before contacting the cell with the inhibitor. E37. The method of embodiment E36, wherein the reference cell is preserved with formalin- fixed paraffin embedded (FFPE) tissue. 5 E38. The method of any one of embodiments E1 to E33, wherein the experimental cell is not preserved before contacting the cell with the inhibitor. E39. The method of any one of embodiments E5 to E35 or E38, wherein the reference cell is not preserved before contacting the cell with the inhibitor. E40. The method of any one of embodiments E1 to E39, wherein the experimental cell is 10 homologous recombination (HR) proficient. E41. The method of any one of embodiments E5 to E40, wherein the reference cell is HR proficient. E42. The method of any one of embodiments E1 to E39, wherein the experimental cell is HR deficient. 15 E43. The method of any one of embodiments E1 to E39 or E42, wherein the reference cell is HR deficient. E44. The method of any one of embodiments E1 to E43, wherein the experimental CIP2A signal intensity is measured in the nucleus of the experimental cell. E45. The method of any one of embodiments E5 to E44, wherein the reference CIP2A signal 20 intensity is measured in the nucleus of the reference cell. E46. The method of any one of embodiments E1 to E45, wherein the reference CIP2A signal intensity is about 1% of mitotic events having a CIP2A foci number greater than a threshold value. E47. The method of any one of embodiments E1 to E45, wherein the reference CIP2A signal intensity is about 5% of mitotic events having a CIP2A foci number greater than a threshold value. 25 E48. The method of any one of embodiments E1 to E47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 1% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value. E49. The method of any one of embodiments E1 to E47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 5% of 30 mitotic events having a CIP2A foci per mitotic event greater than a threshold value. E50. The method of any one of embodiments E1 to E47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 10% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value. E51. The method of any one of embodiments E1 to E47, further comprising identifying the 35 inhibitor or the treatment as effective when at least 15% of mitotic events are determined to have a CIP2A foci per mitotic event greater than a threshold value. E52. The method of any one of embodiments E1 to E47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 20% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value. 271 PATENT ATTORNEY DOCKET: 51246-065WO2 E53. The method of any one of embodiments E1 to E47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 30% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value. E54. The method of any one of embodiments E1 to E47, further comprising identifying the 5 inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 40% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value. E55. The method of any one of embodiments E1 to E47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 50% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value. 10 E56. The method of any one of embodiments E46 to E55, wherein the threshold value is at least 5 CIP2A foci per mitotic event. E57. The method of any one of embodiments E46 to E55, wherein the threshold value is at least 10 CIP2A foci per mitotic event. E58. The method of any one of embodiments E1 to E57, wherein the measuring step 15 comprises immunostaining. E59. The method of any one of embodiments E1 to E58, wherein the measuring step comprises an immunofluorescence step or immunohistochemistry step. E60. The method of any one of embodiments E1 to E59, wherein the measuring step comprises staining with DNA topoisomerase 2-binding protein 1 (TOPBP1). 20 E61. The method of any one of embodiments E1 to E60, wherein the measuring step comprises staining with Mediator of DNA damage checkpoint 1 (MDC1). E62. The method of any one of embodiments E1 to E61, wherein the method comprises contacting the cell with the Polθ inhibitor. E63. The method of embodiment E62, wherein the Polθ inhibitor is a compound of formula (I): 25 or a pharmaceutically acceptable salt thereof, wherein V is N or CR; 30 W is optionally substituted C1-6 alkylene, C1-6 alkoxyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L135 is -O-, -NRX1-, optionally substituted C1-6 alkylene, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted allenyl, optionally substituted C2-6 alkynyl, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3- 8 cycloalkylene, RXis halo, amino, optionally substituted C1-6 alkoxyl, optionally substituted acyl, carboxyl, amido, optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally 272 PATENT ATTORNEY DOCKET: 51246-065WO2 substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally 5 substituted C6-10 aryl; Z is a H, halo, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, optionally substituted C2-6 alkenyl, acyl, or amido; and 10 R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl. E64. The method of embodiment E63, 15 wherein V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; 20 X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3-8 cycloalkylene, RXis optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, 25 optionally substituted C3-8 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally 30 substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; and R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally 35 substituted C3-8 cycloalkyl. E65. The method of embodiment E63, wherein V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 40 arylene; 273 PATENT ATTORNEY DOCKET: 51246-065WO2 X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene; L1is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 5 Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; and 10 R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl. E66. The method of embodiment E63, or pharmaceutically acceptable salt thereof, wherein 15 V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or 20 optionally substituted C6-10 arylene; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 25 heteroaryl, or optionally substituted C6-10 aryl; and R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl. 30 E67. The method of any one of embodiments E63 to E66, wherein W is ethylene, ethynylene, or cyclopropylene. E68. The method of any one of embodiments E63 to E67, wherein V is N. E69. The method of any one of embodiments E63 to E68, wherein the Polθ inhibitor is a compound of formula (II): 35 or a pharmaceutically acceptable salt thereof. E70. The method of any one of embodiments E63 to E68, wherein the Polθ inhibitor is a compound of formula (III): 274 PATENT ATTORNEY DOCKET: 51246-065WO2 or a pharmaceutically acceptable salt thereof. E71. The method of any one of embodiments E61 to E65, wherein V is CR. 5 E72. The method of embodiment E71, wherein V is CH. E73. The method of embodiment E63 to E67, E71, or E72, wherein the Polθ inhibitor is a compound of formula (IV): , 10 or a pharmaceutically acceptable salt thereof. E74. The method of any one of embodiments E63 to E67, E71, or E72, wherein the Polθ inhibitor is a compound of formula (V): , 15 or a pharmaceutically acceptable salt thereof. E75. The method of embodiment E63, wherein the Polθ inhibitor is a compound of formula (VI): , 20 or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl or a C4-C9 heterocyclyl optionally substituted with oxo; 25 RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH. E76. The method of embodiment E63, wherein the Polθ inhibitor is a compound of formula 30 (VII): 275 PATENT ATTORNEY DOCKET: 51246-065WO2 , or a pharmaceutically acceptable salt thereof, wherein 5 n is 0 or 1; o is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl, C1-C6 perfluoroalkyl, halo, or a C4-C9 heterocyclyl optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; 10 RA3is hydrogen or a halogen; RA4is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-C9 cycloalkyl, optionally substituted C3-C9 heterocyclylene, halo, trifluoromethyl, CN, or optionally substituted C2-9 heteroarylene; or the bond between RA4and the cycloalkyl is an alkene. 15 each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH. E77. The method of embodiment E62, wherein a prodrug of the Polθ inhibitor is contacted with the cell. E78. The method of embodiment E77, wherein the Polθ inhibitor prodrug is of formula (PI) 20 (PI), or a pharmaceutically acceptable salt thereof wherein: 25 is an alkene of either E or Z isomeric configuration; V is N or CR; W is optionally substituted C1-6 alkylene, C1-6 alkoxyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl; 30 X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C1-6 alkylene, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted allenyl, optionally substituted C2-6 alkynyl, optionally 276 PATENT ATTORNEY DOCKET: 51246-065WO2 substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3- 8 cycloalkylene, RXis amino, halo, optionally substituted C1-6 alkoxyl, optionally substituted acyl, carboxyl, amido, optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 5 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, halo, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally 10 substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, optionally substituted C2-6 alkenyl, acyl, or amido; R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or 15 C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl; and M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, –RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is independently optionally substituted C1-6 alkyl, and each RM2is independently H, optionally substituted 20 C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl. E79. The method of embodiment E78, wherein V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 25 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3-8 cycloalkylene, RXis optionally substituted C1-6 alkyl, optionally substituted 30 C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; 35 Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10; R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or 277 PATENT ATTORNEY DOCKET: 51246-065WO2 C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl; and M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, –RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is 5 independently optionally substituted C1-6 alkyl, and each RM2is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl. E80. The method of embodiment E78, wherein V is N or CR; 10 W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene; 15 L1is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally 20 substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally 25 substituted C3-8 cycloalkyl; and M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, –RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is independently optionally substituted C1-6 alkyl, and each RM2is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl. 30 E81. The method of embodiment E78, wherein V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; 35 X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; 278 PATENT ATTORNEY DOCKET: 51246-065WO2 Z is a H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; and R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 5 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl; and M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, –RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is 10 independently optionally substituted C1-6 alkyl, and each RM2is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl. E82. The method of any one of embodiments E77 to E81, wherein the Polθ inhibitor prodrug is a compound of formula (PIIb): 15 or a pharmaceutically acceptable salt thereof. E83. The method of any one of embodiments E77 to E81, wherein the Polθ inhibitor prodrug is a compound of formula (PIIIb): 20 (PIIIb) or a pharmaceutically acceptable salt thereof. E84. The method of any one of embodiments E77 to E81, wherein the Polθ inhibitor prodrug is a compound of formula (PIVb): , 25 or a pharmaceutically acceptable salt thereof. E85. The method of any one of embodiments E77 to E81, wherein the Polθ inhibitor prodrug is a compound of formula (PVb): 279 PATENT ATTORNEY DOCKET: 51246-065WO2 , or a pharmaceutically acceptable salt thereof. E86. The method of embodiment E77 or E78, wherein the Polθ inhibitor prodrug is a 5 compound of formula (PVIb): , or a pharmaceutically acceptable salt thereof, wherein 10 n is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl or a C4-C9 heterocyclyl optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; 15 each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH. E87. The method of embodiment E77 or E78, wherein the Polθ inhibitor prodrug is a compound of formula (PVIIb): , 20 280 PATENT ATTORNEY DOCKET: 51246-065WO2 or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; o is 0 or 1; 5 RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl, C1-C6 perfluoroalkyl, halo, or a C4-C9 heterocyclyl optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; RA4is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally 10 substituted C2-6 alkynyl, optionally substituted C3-C9 cycloalkyl, optionally substituted C3-C9 heterocyclylene, halo, trifluoromethyl, CN, or optionally substituted C2-9 heteroarylene; or the bond between RA4and the cycloalkyl is an alkene; each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH. 15 E88. The method of any one of embodiments E1 to E63, wherein the Polθ inhibitor, or a prodrug of the Polθ inhibitor is a compound selected from Table 1. E89. The method of any one of embodiments E1 to E62, wherein the Polθ inhibitor, or a prodrug of the Polθ inhibitor is a compound selected from Table 2. E90. The method of any one of embodiments E1 to E89, wherein the method comprises 20 contacting the cell with the PARP inhibitor. E91. The method of embodiment E90, wherein the PARP inhibitor is selected from the group consisting of talazoparib, niraparib, rucaparib, olaparib, AZD5305, veliparib, iniparib, 2X-121, CEP- 9722, AZD9574, pamiparib, DSB1559, EIK1003, HRS-1167, HS-10502, LAE119, SNV1521 and pharmaceutically acceptable salts or isotopically enriched variants thereof. 25 E92. The method of embodiment E91, wherein the PARP inhibitor is a compound of formula (III): , wherein 30 X1and X2are each independently selected from N and C(H), X3is independently selected from N and C(R4), wherein R4is H or fluoro, R1is C1-4 alkyl or C1-4 fluoroalkyl, R2is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl, and R3is H or C1-4 alkyl, 35 or a pharmaceutically acceptable salt thereof 281 PATENT ATTORNEY DOCKET: 51246-065WO2 provided that: when X1is N, then X2is C(H), and X3is C(R4), when X2is N, then X1═C(H), and X3is C(R4), and when X3is N, then X1and X2are both C(H). 5 or formula (IV), wherein R1 is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C1-4 fluoroalkyl, and C1-4 10 alkyloxy; R2 is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl; R3 is H or C1-4 alkyl; and R4 is halo or C1-4 alkyl, or a pharmaceutically acceptable salt thereof. 15 E93. The method of embodiment E92, wherein the PARP inhibitor is: 5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2-carboxamide, 20 6-chloro-5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- 25 pyridine-2-carboxamide, 6-chloro-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 6-ethyl-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- 30 carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-6- (trifluoromethyl)pyridine-2-carboxamide, 6-(difluoromethyl)-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, 35 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 282 PATENT ATTORNEY DOCKET: 51246-065WO2 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 5 6-chloro-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2- carboxamide, 6-chloro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1- 10 yl]pyridine-2-carboxamide, 6-fluoro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1- yl]pyridine-2-carboxamide, N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, 15 6-chloro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, 6-fluoro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- 20 pyridine-2-carboxamide, 5-[4-[[2-(1,1-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine- 2-carboxamide, 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine- 2-carboxamide, 25 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2-carboxamide, 5-[4-[[2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-fluoro-5-[4-[[2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl- 30 pyridine-2-carboxamide, N-methyl-5-[4-[[3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine- 2-carboxamide, 6-fluoro-N-methyl-5-(4-((3-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-6-yl)methyl) piperazin-1-yl)picolinamide, 35 or a pharmaceutically acceptable salt thereof. E94. The method of embodiment E90, wherein the PARP inhibitor is 5-[4-[(7-ethyl-6-oxo-5H- 1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof. 40 E95. The method of embodiment E90, wherein the PARP inhibitor is: 283 PATENT ATTORNEY DOCKET: 51246-065WO2 6-(difluoromethyl)-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-6 (trifluoromethyl)pyridine-2-carboxamide, 5 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, N-ethyl-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, or a pharmaceutically acceptable salt thereof. 10 E96. The method of embodiment E90, wherein the PARP inhibitor is 5-[4-[(7-ethyl-6-oxo-5H- 1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof. E97. The method of embodiment E90, wherein the PARP inhibitor is: 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine- 15 2- carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 20 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridine-2- carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2- 25 carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 30 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2- carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine- 35 2- carboxamide, 6-fluoro-5-[4-[[5-fluoro-2-[(1 S and 1 R)-1 -fluoroethyl]-3-oxo-4H-quinoxalin-6- yl]methyl]piperazin-1 -yl]-N- methyl-pyridine-2-carboxamide, 5-[4-[[5-fluoro-2-[(1 S and 1 R)-1 -fluoroethyl]-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]- N,6- dimethyl-pyridine-2-carboxamide, 284 PATENT ATTORNEY DOCKET: 51246-065WO2 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2- carboxamide, 5 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2- carboxamide, 5-[4-[[2-(1 ,1-difluoroethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N, 6- dimethyl- pyridine-2-carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-10 pyridine-2- carboxamide, 6-(difluoromethyl)-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- 15 carboxamide, 6-(difluoromethyl)-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl- pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2- 20 carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2- carboxamide, 6-chloro-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 25 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine- 30 2- carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 35 6-chloro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 6-fluoro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- 40 carboxamide, 285 PATENT ATTORNEY DOCKET: 51246-065WO2 5-[4-[[2-(difluoromethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N, 6- dimethyl- pyridine-2-carboxamide, 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5 6-fluoro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine- 2-carboxamide, 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2- carboxamide, 6-chloro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- 10 pyridine- 2-carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine- 2- carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2- carboxamide, 15 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, N-ethyl-6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]pyridine-2- carboxamide, N-ethyl-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl- 20 pyridine-2- carboxamide, 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N, 6- dimethyl- pyridine-2-carboxamide, 6-fluoro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N- methyl- pyridine-2-carboxamide, 25 6-chloro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N- methyl- pyridine-2-carboxamide, 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- 30 pyridine- 2-carboxamide, 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2- carboxamide, 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine- 2- carboxamide, 35 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N- methyl- pyridine-2-carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2- carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- 40 pyridine-2- carboxamide, 286 PATENT ATTORNEY DOCKET: 51246-065WO2 5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2- carboxamide, 6-fluoro-5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine- 2-carboxamide, 5 6-(difluoromethyl)-5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]- N- methyl-pyridine-2-carboxamide, 6-(difluoromethyl)-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl- pyridine-2-carboxamide, or a pharmaceutically acceptable salts thereof. 10 E98. The method of embodiment E90, wherein the PARP inhibitor is 6-fluoro-5-[4-[(5-fluoro-2- methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof. E99. The method of embodiment E90, wherein the PARP inhibitor is 6-fluoro-5-[4-[(5-fluoro-2- methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide. 15 E100. The method of embodiment E89, wherein the PARP inhibitor is a compound selected from Table 3. E101. The method of any one of embodiments E1 to E100, wherein the method comprises contacting the cell with the PARP inhibitor and the Polθ inhibitor simultaneously. E102. The method of any one of embodiments E1 to E100, wherein the method comprises 20 contacting the cell with the PARP inhibitor and the Polθ inhibitor sequentially. E103. The method of any one of embodiments E1 to E102, wherein the method further comprises administering an additional anticancer therapy. E104. The method of embodiment E103, wherein the additional anticancer therapy is a radiotherapy, a radioligand, an ADC, an immune checkpoint inhibitor, a DNA-PK inhibitor, an ATM 25 inhibitor, an ATR inhibitor, a wee1 inhibitor, a PKMYT1 inhibitor, or a CHK1 inhibitor. E105. The method of embodiment E104, wherein the radioligand is selected from the group consisting of zevalin, actimab-A, iomab-ACT, iomab-B, lutetium-177-DOTAGA-PEG-IAC, tozaride, SS0110, BAY-2701439,177Lu-rhPSMA-10.1, CTT-1403, iopofosine, SAR-BBN, SAR-bisPSMA, SARTATE, FAP-2286, CONV-01-α,177Lu-PSMA-I&T, FPI-2059, FPI-1434, FPI-1966, [177Lu] 30 ludotadipep,161Tb-PSMA-I&T, ITM-31, ITM-11, JNJ-69086420, I-131-1095, azedra, PSMA TTC / BAY- 2315497,177Lu-DOTA-EB-TATE, betalutin, AAA817, AAA603, lutathera, pluvicto, PPMX-T002, 186RNL, PNT2003, CAM-H2, AlphaMedix, RYZ101, Sn-117m-DTPA, TLX592, TLX66, TLX250, TLX591, TLX101,124I-omburtamab, GD2-SADA,131I-omburtamab, and pharmaceutically acceptable salts thereof. 35 E106. The method of embodiment E104, wherein the ADC is selected from the group consisting of disitamab vedotin, belantamab mafodotin, trastuzumab deruxtecan, ujvira, mirvetuximab soravtansine, gemtuzumab ozogamicin, enfortumab vedotin, inotuzumab ozogamicin, trastuzumab emtansine, tisotumab vedotin, sacituzumab govitecan, polatuzumab vedotin, loncastuximab tesirine, brentuximab vedotin, PF-06804103, MGTA-117, FOR46, MRG001, SOT102, ZV0203, AOC 1020, 40 PRO1184, BAT8009, BB-1705, JS107, SHR-A1912, CMG901, ladiratuzumab vedotin, BAT8006, 287 PATENT ATTORNEY DOCKET: 51246-065WO2 RC108, BAT8008, mipasetamab uzoptirine, NBE-002, zanidatamab zovodotin, F0002-ADC, SKB315, GQ1001, ABBV-637, XMT-2056, TORL-1-23, FDA022, DYNE-251, STI-6129, ozuriftamab vedotin, farletuzumab ecteribulin, trastuzumab vedotin, DB-1303, OMTX705, TRS005, ispectamab debotansine, DXC-005, ESG-401, ARX788, BAT8010, tusamitamab ravtansine, ABBV-154, 5 naratuximab emtansine, PSMA ADC, TAK-164, ADCT-602, ADCT-901, SHR-A1201, GB251, ABL202, SHR-A1921, 9MW2821, HS-20093, BIO-106, SKB264, camidanlumab tesirine, datopotamab deruxtecan, telisotuzumab vedotin, L-DOS47, AVID100, OBI-999, DP303c, AURIXIM, MT-8633, IMGC936, BB-1701, AOC 1001, JS108, TAC-001, SYSA1801, SHR-A2009, TORL-2-307-ADC, BL- M07D1, STRO-001, A166, mecbotamab vedotin, trastuzumab duocarmazine, ASN004, ABBV-011,10 mirzotamab clezutoclax, OBT076, HS630, SGN-STNV, FDA018, ABBV-400, AZD8205, IBI-343, SGN- ALPV, TAK-500, JBH492, ALT-P7, ifinatamab deruxtecan, DXC-004, IMGN151, XMT-1660, M1231, LM-102, ORM-5029, STI-3258, SGN-B7H4V, TPX-4589, IKS03, zilovertamab vedotin, ARX517, pivekimab sunirine, lonigutamab ugodotin, TRPH-222, MRG004a, DS-6000a, REGN5093-M114, trastuzumab imbotolimod, RC88, HTI-1066, BI-CON-02, SGN-CD228A, AOC 1044, DB-1305, ABBV- 15 319, patritumab deruxtecan, RC118, trastuzumab rezetecan, ARX305, upifitamab rilsodotin, NBT828, TAA013, BL-B01D1, BL-M02D1, GQ1007, DS-9606a, NBT508, B003, DX126-262, XB002, FS-1502, praluzatamab ravtansine, AMT-151, M9140, indatuximab ravtansine, cofetuzumab pelidotin, RG7861, AGS62P1, CX-2029, SGN-B6A, RC98 ADC, DYNE-101, SHR-A1904, anetumab ravtansine, vobramitamab duocarmazine, luveltamab tazevibulin, serclutamab talirine, MRG003, SYD1875, 20 BYON3521, SGN-PDL1V, JSKN-003, YL201, HS-20089, DXC-007, SYS6002, and HDP-101. E107. The method of embodiment E104, wherein the immune checkpoint inhibitor is selected from the group consisting of anti CTLA-4 ipilimumab, anti PD-1 nivolumab, anti PD-1 pembrolizumab, anti PD-1 cemiplimab, anti PD-L1 atezolizumab, anti PD-L1 avelumab, and anti PD-L1 durvalumab. E108. The method of embodiment E104, wherein the DNA-PK inhibitor is selected from the 25 group consisting of AZD-7648, peposertib, M9831, IMP11, NU5455, BAY-8400, ZL-2201, XRD-0394, avadomide, CC-115, KU57788, ZSTK474, LY3023414, BR101801, XRD-0394, NK-314, and pharmaceutically acceptable salts thereof. Other Embodiments 30 Various modifications and variations of the described disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the disclosure. Although the disclosure has been described in connection with specific embodiments, it should be understood that the disclosure as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the disclosure that are obvious to those skilled 35 in the art are intended to be within the scope of the disclosure. Other embodiments are in the claims. 288

Claims

1. PATENT ATTORNEY DOCKET: 51246-065WO2 Claims 1. A method of evaluating the pharmacodynamic activity of an inhibitor selected from a Polθ inhibitor or a PARP inhibitor, comprising: (a) contacting an experimental cell with the inhibitor; (b) measuring an experimental CIP2A signal intensity in the experimental cell; and (c) comparing the experimental CIP2A signal intensity to a reference CIP2A signal intensity; wherein the experimental CIP2A signal intensity is proportional to proportional to the accumulation of CIP2A foci in the experimental cell, and the pharmacodynamic activity of the inhibitor is proportional to the difference between the experimental CIP2A signal intensity and the reference CIP2A signal intensity.

2. The method of claim 1, wherein the experimental cell is obtained from an experimental tissue biopsy on a subject prior to step (a).

3. The method of claim 2, wherein the tissue biopsy is a tumor biopsy and the experimental cell is a tumor cell.

4. A method of measuring the efficacy of a treatment of a subject with an inhibitor selected from a Polθ inhibitor or a PARP inhibitor, the method comprising (a) obtaining an experimental tissue biopsy from the subject; (b) contacting an experimental cell from the experimental tissue biopsy the cell with the inhibitor; (c) measuring an experimental CIP2A signal intensity in the experimental cell; and (d) comparing the experimental CIP2A signal intensity with a reference CIP2A signal intensity; wherein the treatment is more effective if the experimental signal intensity is greater than the reference signal intensity.

5. The method of any one of claims 1 to 4, wherein the reference CIP2A signal intensity is measured in a reference cell.

6. The method of claim 5, wherein the reference cell is obtained from a reference tissue biopsy.

7. The method of claim 6, wherein the reference tissue biopsy is a tumor biopsy and the reference cell is a tumor cell.

8. The method of claim 5, wherein the reference cell is a wild type cell.

9. The method of claim 5, wherein the reference cell is obtained from the experimental tissue biopsy.

10. The method of any one of claims 5 to 9, wherein the reference cell is not contacted with a Polθ inhibitor or a PARP inhibitor prior to measuring the reference signal intensity. 289 PATENT ATTORNEY DOCKET: 51246-065WO2 11. The method of any one of claims 5 to 10, wherein the reference signal intensity is proportional to the CIP2A foci per mitotic event in the reference cell when the reference cell is contacted with a different inhibitor than the experimental cell.

12. The method of any one of claims 5 to 11, wherein the reference signal intensity is proportional to the CIP2A foci per mitotic event obtained with a Polθ inhibitor or a PARP inhibitor different from the experimental cell.

13. A method of measuring the efficacy of a treatment of a subject with an inhibitor selected from a Polθ inhibitor or a PARP inhibitor, the method comprising (a) obtaining a reference tissue biopsy from the subject, the reference tissue biopsy comprising a reference cell; (b) measuring a reference CIP2A signal intensity from the reference cell; (c) administering the inhibitor to the subject; (d) allowing a duration of treatment to elapse; (e) obtaining an experimental tissue biopsy from the subject, the experimental tissue biopsy comprising an experimental cell; (f) contacting the experimental cell with the inhibitor; (g) measuring an experimental CIP2A signal intensity in the experimental cell; and (h) comparing the experimental CIP2A signal intensity with a reference CIP2A signal intensity; wherein the treatment is more effective if the experimental CIP2A signal intensity is greater than the reference CIP2A signal intensity.

14. The method of claim 13, wherein the duration of treatment is at least 1 day.

15. The method of claim 13, wherein the duration of treatment is at least 10 days.

16. The method of claim 13, wherein the duration of treatment is at least 20 days.

17. The method of claim 13, wherein the duration of treatment is at least 30 days.

18. The method of claim 13, wherein the duration of treatment is at least 45 days.

19. The method of claim 13, wherein the duration of treatment is at least 60 days.

20. The method of any one of claims 13 to 19, wherein the inhibitor is administered continuously to the subject throughout the duration of treatment.

21. The method of any one of claims 13 to 19, wherein the inhibitor is administered on a dosing schedule to the subject throughout the duration of treatment. 290 PATENT ATTORNEY DOCKET: 51246-065WO2 22. The method of any one of claims 13 to 21, wherein the reference tissue biopsy is a tumor biopsy and the reference cell is a tumor cell.

23. The method of any one of claims 13 to 22, wherein the reference cell is not contacted with a Polθ inhibitor or a PARP inhibitor prior to measuring the reference signal intensity.

24. The method of any one of claims 2 to 23, wherein the experimental tissue biopsy is a tumor biopsy and the experimental cell is a tumor cell.

25. The method of any one of claims 2 to 24, wherein the subject is suffering from a disease or disorder.

26. The method of claim 25, wherein the disease or disorder is cancer.

27. The method of claim 26, wherein the cancer is a carcinoma, sarcoma, adenocarcinoma, leukemia, lymphoma, or melanoma.

28. The method of claim 27, wherein the cancer is a carcinoma selected from the group consisting of medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma 291 PATENT ATTORNEY DOCKET: 51246-065WO2 telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum.

29. The method of claim 27, wherein the cancer is a sarcoma selected from the group consisting of chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy’s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

30. The method of claim 27, wherein the cancer is a leukemia selected from the group consisting of nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

31. The method of claim 27, wherein the cancer is a melanoma selected from the group consisting of acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

32. The method of claim 27, wherein the cancer is prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head & neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterus cancer, medulloblastoma, colorectal cancer, or pancreatic cancer.

33. The method of claim 27, wherein the cancer is Hodgkin's disease, Non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, malignant 292 PATENT ATTORNEY DOCKET: 51246-065WO2 pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

34. The method of any one of claims 1 to 33, wherein the experimental cell is preserved before contacting the cell with the inhibitor.

35. The method of claim 34, wherein the experimental cell is preserved with formalin-fixed paraffin embedded (FFPE) tissue.

36. The method of any one of claims 5 to 35, wherein the reference cell is preserved before contacting the cell with the inhibitor.

37. The method of claim 36, wherein the reference cell is preserved with formalin-fixed paraffin embedded (FFPE) tissue.

38. The method of any one of claims 1 to 33, wherein the experimental cell is not preserved before contacting the cell with the inhibitor.

39. The method of any one of claims 5 to 35 or 38, wherein the reference cell is not preserved before contacting the cell with the inhibitor.

40. The method of any one of claims 1 to 39, wherein the experimental cell is homologous recombination (HR) proficient.

41. The method of any one of claims 5 to 40, wherein the reference cell is HR proficient.

42. The method of any one of claims 1 to 39, wherein the experimental cell is HR deficient.

43. The method of any one of claims 1 to 39 or 42, wherein the reference cell is HR deficient.

44. The method of any one of claims 1 to 43, wherein the experimental CIP2A signal intensity is measured in the nucleus of the experimental cell.

45. The method of any one of claims 5 to 44, wherein the reference CIP2A signal intensity is measured in the nucleus of the reference cell.

46. The method of any one of claims 1 to 45, wherein the reference CIP2A signal intensity is about 1% of mitotic events having a CIP2A foci number greater than a threshold value. 293 PATENT ATTORNEY DOCKET: 51246-065WO2 47. The method of any one of claims 1 to 45, wherein the reference CIP2A signal intensity is about 5% of mitotic events having a CIP2A foci number greater than a threshold value.

48. The method of any one of claims 1 to 47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 1% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value.

49. The method of any one of claims 1 to 47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 5% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value.

50. The method of any one of claims 1 to 47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 10% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value.

51. The method of any one of claims 1 to 47, further comprising identifying the inhibitor or the treatment as effective when at least 15% of mitotic events are determined to have a CIP2A foci per mitotic event greater than a threshold value.

52. The method of any one of claims 1 to 47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 20% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value.

53. The method of any one of claims 1 to 47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 30% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value.

54. The method of any one of claims 1 to 47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 40% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value.

55. The method of any one of claims 1 to 47, further comprising identifying the inhibitor or the treatment as effective when the experimental CIP2A signal intensity is at least 50% of mitotic events having a CIP2A foci per mitotic event greater than a threshold value.

56. The method of any one of claims 46 to 55, wherein the threshold value is at least 5 CIP2A foci per mitotic event.

57. The method of any one of claims 46 to 55, wherein the threshold value is at least 10 CIP2A foci per mitotic event. 294 PATENT ATTORNEY DOCKET: 51246-065WO2 58. The method of any one of claims 1 to 57, wherein the measuring step comprises immunostaining.

59. The method of any one of claims 1 to 58, wherein the measuring step comprises an immunofluorescence step or immunohistochemistry step.

60. The method of any one of claims 1 to 59, wherein the measuring step comprises staining with DNA topoisomerase 2-binding protein 1 (TOPBP1).

61. The method of any one of claims 1 to 60, wherein the measuring step comprises staining with Mediator of DNA damage checkpoint 1 (MDC1).

62. The method of any one of claims 1 to 61, wherein the method comprises contacting the cell with the Polθ inhibitor.

63. The method of claim 62, wherein the Polθ inhibitor is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein V is N or CR; W is optionally substituted C1-6 alkylene, C1-6 alkoxyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C1-6 alkylene, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted allenyl, optionally substituted C2-6 alkynyl, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3-8 cycloalkylene, RXis halo, amino, optionally substituted C1-6 alkoxyl, optionally substituted acyl, carboxyl, amido, optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, halo, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, optionally substituted C2-6 alkenyl, acyl, or amido; and R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein 295 PATENT ATTORNEY DOCKET: 51246-065WO2 each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl.

64. The method of claim 63, wherein V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3-8 cycloalkylene, RXis optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; and R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl.

65. The method of claim 63, wherein V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene; L1is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6alkoxy, optionally substituted C3-8cycloalkyl, optionally substituted C2-9heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; and R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein 296 PATENT ATTORNEY DOCKET: 51246-065WO2 each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl.

66. The method of claim 63, or pharmaceutically acceptable salt thereof, wherein V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; and R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl.

67. The method of any one of claims 63 to 66, wherein W is ethylene, ethynylene, or cyclopropylene.

68. The method of any one of claims 63 to 67, wherein V is N.

69. The method of any one of claims 63 to 68, wherein the Polθ inhibitor is a compound of formula (II): or a pharmaceutically acceptable salt thereof.

70. The method of any one of claims 63 to 68, wherein the Polθ inhibitor is a compound of formula (III): or a pharmaceutically acceptable salt thereof.

71. The method of any one of claims 61 to 65, wherein V is CR. 297 PATENT ATTORNEY DOCKET: 51246-065WO2 72. The method of claim 71, wherein V is CH.

73. The method of claim 63 to 67, 71, or 72, wherein the Polθ inhibitor is a compound of formula (IV): , or a pharmaceutically acceptable salt thereof.

74. The method of any one of claims 63 to 67, 71, or 72, wherein the Polθ inhibitor is a compound of formula (V): , or a pharmaceutically acceptable salt thereof.

75. The method of claim 63, wherein the Polθ inhibitor is a compound of formula (VI): , or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl or a C4-C9 heterocyclyl optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH.

76. The method of claim 63, wherein the Polθ inhibitor is a compound of formula (VII): 298 PATENT ATTORNEY DOCKET: 51246-065WO2 , or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; o is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl, C1-C6 perfluoroalkyl, halo, or a C4-C9 heterocyclyl optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; RA4is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-C9 cycloalkyl, optionally substituted C3-C9 heterocyclylene, halo, trifluoromethyl, CN, or optionally substituted C2-9 heteroarylene; or the bond between RA4and the cycloalkyl is an alkene. each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH.

77. The method of claim 62, wherein a prodrug of the Polθ inhibitor is contacted with the cell.

78. The method of claim 77, wherein the Polθ inhibitor prodrug is of formula (PI) (PI), or a pharmaceutically acceptable salt thereof wherein: is an alkene of either E or Z isomeric configuration; V is N or CR; W is optionally substituted C1-6 alkylene, C1-6 alkoxyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10 aryl; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C1-6 alkylene, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted allenyl, optionally substituted C2-6 alkynyl, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3-8 299 PATENT ATTORNEY DOCKET: 51246-065WO2 cycloalkylene, RXis amino, halo, optionally substituted C1-6 alkoxyl, optionally substituted acyl, carboxyl, amido, optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9heteroaryl, optionally substituted C3-8cycloalkyl C1-6alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, halo, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, optionally substituted C2-6 alkenyl, acyl, or amido; R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl; and M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, – RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is independently optionally substituted C1-6 alkyl, and each RM2is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl.

79. The method of claim 78, wherein V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene, wherein X is further optionally substituted with -L1-RX, wherein L1is -O-, -NRX1-, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C3-8 cycloalkylene, RXis optionally substituted C1-6 alkyl, optionally substituted C2-6 heteroalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C3-8 cycloalkyl C1-6 alkyl, or optionally substituted C2-9 heteroaryl C1-6 alkyl, and RX1is hydrogen or optionally substituted C1-6 alkyl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10; R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6alkyl, or optionally substituted C3-8cycloalkyl; and M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, – RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is independently optionally 300 PATENT ATTORNEY DOCKET: 51246-065WO2 substituted C1-6 alkyl, and each RM2is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl.

80. The method of claim 78, wherein V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene; L1is optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; R is hydrogen, halogen, optionally substituted C1-6 alkyl, CN, optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl; and M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, – RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is independently optionally substituted C1-6 alkyl, and each RM2is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl.

81. The method of claim 78, wherein V is N or CR; W is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, or optionally substituted C6-10 arylene; X is optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, or optionally substituted C6-10 arylene; Y is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl; Z is a H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, or optionally substituted C6-10 aryl; and R is hydrogen, halogen, optionally substituted C1-6alkyl, CN, optionally substituted C3-8cycloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkoxy, N(R1)2, or C(O)NH2, wherein each R1is independently hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-8 cycloalkyl; and 301 PATENT ATTORNEY DOCKET: 51246-065WO2 M is optionally substituted C1-6 alkylphosphonyl, optionally substituted C1-6 alkylacylphosphonyl, – RM1–O–C(O)–RM1–CO2H, or –RM1–O–C(O)–RM1-N(RM2)2, wherein each RM1is independently optionally substituted C1-6alkyl, and each RM2is independently H, optionally substituted C1-6alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C3-8 heterocycloalkyl.

82. The method of any one of claims 77 to 81, wherein the Polθ inhibitor prodrug is a compound of formula (PIIb): or a pharmaceutically acceptable salt thereof.

83. The method of any one of claims 77 to 81, wherein the Polθ inhibitor prodrug is a compound of formula (PIIIb): (PIIIb) or a pharmaceutically acceptable salt thereof.

84. The method of any one of claims 77 to 81, wherein the Polθ inhibitor prodrug is a compound of formula (PIVb): , or a pharmaceutically acceptable salt thereof.

85. The method of any one of claims 77 to 81, wherein the Polθ inhibitor prodrug is a compound of formula (PVb): , or a pharmaceutically acceptable salt thereof. 302 PATENT ATTORNEY DOCKET: 51246-065WO2 86. The method of claim 77 or 78, wherein the Polθ inhibitor prodrug is a compound of formula (PVIb): , or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl or a C4-C9 heterocyclyl optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; RA3is hydrogen or a halogen; each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH.

87. The method of claim 77 or 78, wherein the Polθ inhibitor prodrug is a compound of formula (PVIIb): , or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1; o is 0 or 1; RA1is a C2-C9 heteroaryl optionally substituted with C1-C6 alkyl, C1-C6 perfluoroalkyl, halo, or a C4-C9 heterocyclyl optionally substituted with oxo; RA2is a C1-C6 alkyl, C1-C6 alkoxy, or halogen; 303 PATENT ATTORNEY DOCKET: 51246-065WO2 RA3is hydrogen or a halogen; RA4is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-C9cycloalkyl, optionally substituted C3-C9heterocyclylene, halo, trifluoromethyl, CN, or optionally substituted C2-9 heteroarylene; or the bond between RA4and the cycloalkyl is an alkene; each of X1and V is independently N or CH; and is a single bond, X2is N, and X3is CO, or is a double bond, X2is C, and X3is N or CH.

88. The method of any one of claims 1 to 63, wherein the Polθ inhibitor, or a prodrug of the Polθ inhibitor is a compound selected from Table 1.

89. The method of any one of claims 1 to 62, wherein the Polθ inhibitor, or a prodrug of the Polθ inhibitor is a compound selected from Table 2.

90. The method of any one of claims 1 to 89, wherein the method comprises contacting the cell with the PARP inhibitor.

91. The method of claim 90, wherein the PARP inhibitor is selected from the group consisting of talazoparib, niraparib, rucaparib, olaparib, AZD5305, veliparib, iniparib, 2X-121, CEP-9722, AZD9574, pamiparib, DSB1559, EIK1003, HRS-1167, HS-10502, LAE119, SNV1521 and pharmaceutically acceptable salts or isotopically enriched variants thereof.

92. The method of claim 91, wherein the PARP inhibitor is a compound of formula (III): , wherein X1and X2are each independently selected from N and C(H), X3is independently selected from N and C(R4), wherein R4is H or fluoro, R1is C1-4 alkyl or C1-4 fluoroalkyl, R2is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl, and R3is H or C1-4 alkyl, or a pharmaceutically acceptable salt thereof provided that: when X1is N, then X2is C(H), and X3is C(R4), when X2is N, then X1═C(H), and X3is C(R4), and when X3is N, then X1and X2are both C(H). or formula (IV), 304 PATENT ATTORNEY DOCKET: 51246-065WO2 wherein R1 is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C1-4 fluoroalkyl, and C1-4 alkyloxy; R2 is independently selected from H, halo, C1-4 alkyl, and C1-4 fluoroalkyl; R3 is H or C1-4 alkyl; and R4 is halo or C1-4 alkyl, or a pharmaceutically acceptable salt thereof.

93. The method of claim 92, wherein the PARP inhibitor is: 5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 6-ethyl-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-6-(trifluoromethyl)pyridine- 2-carboxamide, 6-(difluoromethyl)-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 305 PATENT ATTORNEY DOCKET: 51246-065WO2 N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2- carboxamide, 6-chloro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1- yl]pyridine-2-carboxamide, 6-fluoro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1- yl]pyridine-2-carboxamide, N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 6-chloro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, 6-fluoro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine- 2-carboxamide, 5-[4-[[2-(1,1-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2-carboxamide, 5-[4-[[2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-fluoro-5-[4-[[2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine- 2-carboxamide, N-methyl-5-[4-[[3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2- carboxamide, 6-fluoro-N-methyl-5-(4-((3-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-6-yl)methyl) piperazin-1-yl)picolinamide, or a pharmaceutically acceptable salt thereof.

94. The method of claim 90, wherein the PARP inhibitor is 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

95. The method of claim 90, wherein the PARP inhibitor is: 6-(difluoromethyl)-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-6 (trifluoromethyl)pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, N-ethyl-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, 306 PATENT ATTORNEY DOCKET: 51246-065WO2 or a pharmaceutically acceptable salt thereof.

96. The method of claim 90, wherein the PARP inhibitor is 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide or a pharmaceutically acceptable salt thereof.

97. The method of claim 90, wherein the PARP inhibitor is: 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2- carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridine-2- carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2- carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine- 2- carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine- 2- carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 6-fluoro-5-[4-[[5-fluoro-2-[(1 S and 1 R)-1 -fluoroethyl]-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin- 1 -yl]-N- methyl-pyridine-2-carboxamide, 5-[4-[[5-fluoro-2-[(1 S and 1 R)-1 -fluoroethyl]-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N,6- dimethyl-pyridine-2-carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2- carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 5-[4-[[2-(1 ,1-difluoroethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N, 6-dimethyl- pyridine-2-carboxamide, 307 PATENT ATTORNEY DOCKET: 51246-065WO2 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 6-(difluoromethyl)-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 6-(difluoromethyl)-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl- pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2- carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine- 2- carboxamide, 6-chloro-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine- 2- carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 6-chloro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 6-fluoro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[[2-(difluoromethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N, 6-dimethyl- pyridine-2-carboxamide, 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine- 2-carboxamide, 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 6-chloro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine- 2-carboxamide, 308 PATENT ATTORNEY DOCKET: 51246-065WO2 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine- 2- carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, N-ethyl-6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine- 2- carboxamide, N-ethyl-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine- 2- carboxamide, 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N, 6-dimethyl- pyridine-2-carboxamide, 6-fluoro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N- methyl- pyridine-2-carboxamide, 6-chloro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N- methyl- pyridine-2-carboxamide, 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl- pyridine-2- carboxamide, 6-fluoro-5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine- 2-carboxamide, 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine- 2- carboxamide, 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2-carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2- carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide, 5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine- 2- carboxamide, 6-fluoro-5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine- 2-carboxamide, 6-(difluoromethyl)-5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide, 6-(difluoromethyl)-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide, or a pharmaceutically acceptable salts thereof. 309 PATENT ATTORNEY DOCKET: 51246-065WO2 98. The method of claim 90, wherein the PARP inhibitor is 6-fluoro-5-[4-[(5-fluoro-2-methyl-3- oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

99. The method of claim 90, wherein the PARP inhibitor is 6-fluoro-5-[4-[(5-fluoro-2-methyl-3- oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide.

100. The method of claim 89, wherein the PARP inhibitor is a compound selected from Table 3.

101. The method of any one of claims 1 to 100, wherein the method comprises contacting the cell with the PARP inhibitor and the Polθ inhibitor simultaneously.

102. The method of any one of claims 1 to 100, wherein the method comprises contacting the cell with the PARP inhibitor and the Polθ inhibitor sequentially.

103. The method of any one of claims 1 to 102, wherein the method further comprises administering an additional anticancer therapy.

104. The method of claim 103, wherein the additional anticancer therapy is a radiotherapy, a radioligand, an ADC, an immune checkpoint inhibitor, a DNA-PK inhibitor, an ATM inhibitor, an ATR inhibitor, a wee1 inhibitor, a PKMYT1 inhibitor, or a CHK1 inhibitor.

105. The method of claim 104, wherein the radioligand is selected from the group consisting of zevalin, actimab-A, iomab-ACT, iomab-B, lutetium-177-DOTAGA-PEG-IAC, tozaride, SS0110, BAY- 2701439,177Lu-rhPSMA-10.1, CTT-1403, iopofosine, SAR-BBN, SAR-bisPSMA, SARTATE, FAP-2286, CONV-01-α,177Lu-PSMA-I&T, FPI-2059, FPI-1434, FPI-1966, [177Lu] ludotadipep,161Tb-PSMA-I&T, ITM- 31, ITM-11, JNJ-69086420, I-131-1095, azedra, PSMA TTC / BAY-2315497,177Lu-DOTA-EB-TATE, betalutin, AAA817, AAA603, lutathera, pluvicto, PPMX-T002, 186RNL, PNT2003, CAM-H2, AlphaMedix, RYZ101, Sn-117m-DTPA, TLX592, TLX66, TLX250, TLX591, TLX101,124I-omburtamab, GD2-SADA,131I- omburtamab, and pharmaceutically acceptable salts thereof.

106. The method of claim 104, wherein the ADC is selected from the group consisting of disitamab vedotin, belantamab mafodotin, trastuzumab deruxtecan, ujvira, mirvetuximab soravtansine, gemtuzumab ozogamicin, enfortumab vedotin, inotuzumab ozogamicin, trastuzumab emtansine, tisotumab vedotin, sacituzumab govitecan, polatuzumab vedotin, loncastuximab tesirine, brentuximab vedotin, PF-06804103, MGTA-117, FOR46, MRG001, SOT102, ZV0203, AOC 1020, PRO1184, BAT8009, BB-1705, JS107, SHR-A1912, CMG901, ladiratuzumab vedotin, BAT8006, RC108, BAT8008, mipasetamab uzoptirine, NBE-002, zanidatamab zovodotin, F0002-ADC, SKB315, GQ1001, ABBV-637, XMT-2056, TORL-1-23, FDA022, DYNE-251, STI-6129, ozuriftamab vedotin, farletuzumab ecteribulin, trastuzumab vedotin, DB-1303, OMTX705, TRS005, ispectamab debotansine, DXC-005, ESG-401, ARX788, BAT8010, tusamitamab ravtansine, ABBV-154, naratuximab emtansine, PSMA ADC, TAK-164, 310 PATENT ATTORNEY DOCKET: 51246-065WO2 ADCT-602, ADCT-901, SHR-A1201, GB251, ABL202, SHR-A1921, 9MW2821, HS-20093, BIO-106, SKB264, camidanlumab tesirine, datopotamab deruxtecan, telisotuzumab vedotin, L-DOS47, AVID100, OBI-999, DP303c, AURIXIM, MT-8633, IMGC936, BB-1701, AOC 1001, JS108, TAC-001, SYSA1801, SHR-A2009, TORL-2-307-ADC, BL-M07D1, STRO-001, A166, mecbotamab vedotin, trastuzumab duocarmazine, ASN004, ABBV-011, mirzotamab clezutoclax, OBT076, HS630, SGN-STNV, FDA018, ABBV-400, AZD8205, IBI-343, SGN-ALPV, TAK-500, JBH492, ALT-P7, ifinatamab deruxtecan, DXC-004, IMGN151, XMT-1660, M1231, LM-102, ORM-5029, STI-3258, SGN-B7H4V, TPX-4589, IKS03, zilovertamab vedotin, ARX517, pivekimab sunirine, lonigutamab ugodotin, TRPH-222, MRG004a, DS- 6000a, REGN5093-M114, trastuzumab imbotolimod, RC88, HTI-1066, BI-CON-02, SGN-CD228A, AOC 1044, DB-1305, ABBV-319, patritumab deruxtecan, RC118, trastuzumab rezetecan, ARX305, upifitamab rilsodotin, NBT828, TAA013, BL-B01D1, BL-M02D1, GQ1007, DS-9606a, NBT508, B003, DX126-262, XB002, FS-1502, praluzatamab ravtansine, AMT-151, M9140, indatuximab ravtansine, cofetuzumab pelidotin, RG7861, AGS62P1, CX-2029, SGN-B6A, RC98 ADC, DYNE-101, SHR-A1904, anetumab ravtansine, vobramitamab duocarmazine, luveltamab tazevibulin, serclutamab talirine, MRG003, SYD1875, BYON3521, SGN-PDL1V, JSKN-003, YL201, HS-20089, DXC-007, SYS6002, and HDP-101.

107. The method of claim 104, wherein the immune checkpoint inhibitor is selected from the group consisting of anti CTLA-4 ipilimumab, anti PD-1 nivolumab, anti PD-1 pembrolizumab, anti PD-1 cemiplimab, anti PD-L1 atezolizumab, anti PD-L1 avelumab, and anti PD-L1 durvalumab.

108. The method of claim 104, wherein the DNA-PK inhibitor is selected from the group consisting of AZD-7648, peposertib, M9831, IMP11, NU5455, BAY-8400, ZL-2201, XRD-0394, avadomide, CC-115, KU57788, ZSTK474, LY3023414, BR101801, XRD-0394, NK-314, and pharmaceutically acceptable salts thereof. 311

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