MYT1 inhibitors for the treatment of cancers harboring replication stress mutations

Abstract

Disclosed herein are methods of using Myt1 inhibitors, alone and in combination with a second therapeutic agent, to effectively treat RAS (e.g., KRAS) mutant cancers.

Description

[0001] MYT1 INHIBITORS FOR THE TREATMENT OF CANCERS HARBORING REPLICATION STRESS MUTATIONS

[0002] FIELD OF THE INVENTION

[0003] The invention relates to therapies using inhibitors of membrane associated tyrosine and threonine specific Cdc2 inhibitory kinase (Myt1) (gene name PKMYT1) to treat replication stress cancers.

[0004] BACKGROUND

[0005] DNA is continuously subjected to both endogenous insults (e.g., stalled replication forks, reactive oxygen species) and exogenous insults (UV, ionizing radiation, chemical) that can lead to DNA damage. As a result, cells have established sophisticated mechanisms to counteract these deleterious events that would otherwise compromise genomic integrity and lead to genomic instability diseases such as cancer. These mechanisms are collectively referred to as the DNA damage response (DDR). One component of the overall DDR is the activation of various checkpoint pathways that modulate specific DNA-repair mechanisms throughout the various phases of the cell cycle, which includes the G1 , S, G2 and Mitosis checkpoints. A majority of cancer cells have lost their G1 checkpoint owing to p53 mutations and as such, rely on the G2 checkpoint to make the necessary DNA damage corrections prior to committing to enter mitosis and divide into two daughter cells.

[0006] There is a need for new anti-cancer therapeutic approaches, e.g., those utilizing small molecules, especially therapies allowing for targeted cancer treatment.

[0007] SUMMARY OF THE INVENTION

[0008] In general, the present disclosure demonstrates the unexpected efficacy of cancer treatments including multiple sources of replication stress. In particular, the present disclosure relates to the combination of one or more replication stress biomarkers, (e.g., a mutation, gene amplification, or overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c- MYC, l-MYC, n-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAE, or a prior or current infection with the human papillomavirus (HPV)) and one or more therapeutic agents that exacerbate replication stress or prevent cellular recovery from replication stress (e.g., a Myt1 inhibitor, alone or in combination with a second therapeutic agent). The disclosure further highlights methods of using Myt1 inhibitors for the treatment of cancers with a replication stress biomarker, alone and in combination with a second therapeutic agent.

[0009] In a first aspect, the disclosure provides for a method for treating a cancer in a subject, the method including administering to the subject in need thereof a therapeutically effective amount of a membrane-associated tyrosine and threonine-specific Cdc2-inhibatory kinase (Myt1) inhibitor, wherein the cancer includes a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

[0010] In a second aspect, the disclosure provides for a method for treating a cancer in a subject, the method including administering to the subject in need thereof a therapeutically effective amount of a membrane-associated tyrosine and threonine-specific cdc2-inhibatory kinase (Myt1) inhibitor, wherein the cancer includes a cancer previously identified as a cancer comparing a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c- MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

[0011] In a third aspect, the disclosure provides for a method of inducing death in a cancer cell, the method including contacting the cell with an effective amount of a Myt1 inhibitor, wherein the cancer includes a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

[0012] In a fourth aspect, the disclosure provides for a method of inducing death in a cancer cell, the method including contacting the cell with an effective amount of a Myt1 inhibitor, wherein the cancer includes a cancer previously identified as a cancer including a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c- MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

[0013] In some embodiments of the first, second, third, or fourth aspect, the cancer includes a KRAS mutation. In some embodiments, the KRAS mutation encodes for an amino acid substitution in a Kras protein, wherein the amino acid substitution is G12D, G12V, G12C, G13D, G12R, G12A, Q61 H, G12S, A146T, G13C, Q61 L, Q61 R, K117N, A146V, G12F, Q61 K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, or combinations thereof. In some embodiments, the cancer includes colorectal cancer, pancreatic cancer, lung cancer, uterine cancer, ovarian cancer, cervical cancer or gastro-esophageal cancer.

[0014] In some embodiments of the first, second, third, or fourth aspect, the cancer includes KRAS amplification.

[0015] In some embodiments of the first, second, third, or fourth aspect, the cancer includes an HRAS mutation. In some embodiments, the HRAS mutation encodes for an amino acid substitution in an HRAS protein, wherein the amino acid substitution is Q61 R, G13R, Q61 K, G12S, Q61 L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61 H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, or combinations thereof. In some embodiments, the cancer includes kidney cancer, bladder cancer, head and neck cancer, or thyroid cancer.

[0016] In some embodiments of the first, second, third, or fourth aspect, the cancer includes an NRAS mutation. In some embodiments, the NRAS mutation encodes for an amino acid substitution in a NRAS protein, wherein the amino acid substitution is Q61 R, Q61 K, G12D, Q61 L, Q61 H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61 P, A59D, E132K, E49K, T50I, A146V, or A59T, or combinations thereof. In some embodiments, the cancer includes colorectal cancer, thyroid cancer, or melanoma. In some embodiments, the cancer further includes a TP53 mutation.

[0017] In some embodiments, the cancer is uterine cancer, ovarian cancer, cervical cancer, bladder cancer, brain cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, head and neck cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, thyroid cancer, melanoma, or endometrial cancer.

[0018] In some embodiments, the Myt1 inhibitor is a compound of formula (I):

[0019] (I), or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR2;

[0020] R1and each R2are independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Cs-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, cyano, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B; or R1combines with one R2that is vicinal io R1to form an optionally substituted C3-6 alkylene; each of R3and R4is independently optionally substituted C1-6 alkyl or halogen;

[0021] R5is H or -N(R7)2;

[0022] R6is -C(O)NH(R8), -C(O)R7A, or -S02R7A; each R7is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted Cs-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or -SC>2R7A; or two R7groups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R7Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted Cs-w aryl; each R7Bis independently hydroxyl, optionally substituted C1-6 alkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -N(R7)2, -C(O)N(R8)2, - SO2N(R8)2, -SC>2R7A, or optionally substituted alkoxy; each R8is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted Cs-w aryl C1-6 alkyl, optionally substituted Cs-w aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or two R8, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; and

[0023] Q is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, optionally substituted C3-8 cycloalkenylene optionally substituted Cs-w arylene, optionally substituted C2-9 heterocyclylene, or optionally substituted C1-9 heteroarylene; wherein the C2-9 heterocyclyl, C2-9 heterocyclyl C1-6 alkyl, C1-9 heteroaryl, and C1-9 heteroaryl C1-6 alkyl groups each contain one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

[0024] In some embodiments, the compound is enriched for the atropisomer of formula (IA):

[0025] (IA), or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, X is CR2.

[0027] In some embodiments, the compound is of formula (II):

[0028] (II); or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the compound is enriched for the atropisomer of formula (IIA):

[0030] (HA); or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the compound is of formula (III): wherein R2Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Cs-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is enriched for the atropisomer of formula (IIIA): or a pharmaceutically acceptable salt thereof. In some embodiments, R2Ais hydrogen, optionally substituted C1-6 alkyl, or halogen.

[0032] In some embodiments, R3is optionally substituted C1-6 alkyl. In some embodiments, R3is halogen. In some embodiments, the halogen is chlorine.

[0033] In some embodiments, R4is optionally substituted C1-6 alkyl. In some embodiments, R4is halogen. In some embodiments, the halogen is chlorine.

[0034] In some embodiments, R2is hydrogen. In some embodiments, R2is optionally substituted C1-6 alkyl. In some embodiments, R2is optionally substituted methyl or optionally substituted isopropyl. In some embodiments, R2is halogen.

[0035] In some embodiments, R1is hydrogen. In some embodiments, R1is halogen. In some embodiments, R1is chlorine or bromine. In some embodiments, R1is optionally substituted C1-6 alkyl. In some embodiments, R1is optionally substituted methyl, optionally substituted ethyl, optionally substituted isopropyl, or optionally substituted butyl. In some embodiments, R1is optionally substituted C1-9 heteroaryl. In some embodiments, R1is 1 ,3-thiazolyl, 1 ,2-thiazolyl, 1 ,3-oxazolyl, benzo-1 ,3-thiazolyl, benzo-1 ,3-oxazolyl, indolyl, benzimidazolyl, pyridyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, or pyrazolyl, wherein R1is optionally substituted with substituents as defined for optionally substituted C1-9 heteroaryl. In some embodiments, R1is optionally substituted C3-8 cycloalkyl. In some embodiments, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R1is optionally substituted with substituents as defined for optionally substituted C3-8 cycloalkyl. In some embodiments, R1is optionally substituted C2-9 heterocyclyl. In some embodiments, R1is 1 ,2,3,6-tetrahydropyridinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, oxa-aza-spiro[3,3]heptane, or oxa-aza-bicyclo[3.2.1]octane, wherein R1is optionally substituted with substituents as defined for optionally substituted C2-9 heterocyclyl. In some embodiments, R1is optionally substituted C3-8 cycloalkyl. In some embodiments, R1is optionally substituted cyclohexenyl or optionally substituted cyclopentenyl. In some embodiments, R1is optionally substituted CB-IO aryl. In some embodiments, R1is optionally substituted phenyl.

[0036] In some embodiments, R1is -Q-R7B. In some embodiments, Q is optionally substituted C2-6 alkynylene. In some embodiments, Q is optionally substituted C1-6 alkylene. In some embodiments, Q is optionally substituted Cs-w arylene. In some embodiments, R7Bis optionally substituted C2-9 heterocyclyl. In some embodiments, R7Bis optionally substituted Cs-w aryl.

[0037] In some embodiments, R1is optionally substituted with one, two, or three groups independently selected from the group consisting of methyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, -C(O)NH2, -C(O)NH(Me), -C(O)N(Me)2, -(CH2)n-C(O)OH, and -(CH2)n- C(O)Ot-Bu, wherein n is 0 or 1 . In some embodiments, R1is -N(R7)2. In some embodiments, R1is diethylamino. In some embodiments, R5is hydrogen. In some embodiments, R5is -N(R7)2. In some embodiments, R5is -NH2.

[0038] In some embodiments, R6is -C(O)NH(R8). In some embodiments, R6is -C(O)NH2. In some embodiments, R6is -C(O)NH(Me). In some embodiments, R6is -SC>2R7A. In some embodiments, R6is - SO2Me.

[0039] In some embodiments, the Myt1 inhibitor is selected from the group consisting of compounds 1- 328 and pharmaceutically acceptable salts thereof. In some embodiments, the Myt1 inhibitor is administered as a pharmaceutical composition.

[0040] In some embodiments, the method further includes the administration of a therapeutically effective amount of a Wee1 inhibitor, Fen1 inhibitor, Topi inhibitor, Rrm1 inhibitor, Rrm2 inhibitor, Aurkb inhibitor, Top2A inhibitor, Atr inhibitor, Ttk inhibitor, Sod1 inhibitor, Sod2 inhibitor, Bub1 inhibitor, Cdc7 inhibitor, Sae1 inhibitor, Plk1 inhibitor, Uba2 inhibitor, Dut inhibitor, Hdac3 inhibitor, Chekl inhibitor, Aurka inhibitor, Men1 inhibitor, Doti I inhibitor, Crebbp inhibitor, Ezh2 inhibitor, Plk4 inhibitor, Haspin inhibitor, Mettl3 inhibitor, nucleoside analog, platinum-based DNA damaging agent, or a combination thereof.

[0041] In some embodiments, the method includes administering the Wee1 inhibitor. In some

[0042] In some embodiments, the method includes the step of administering the Fen1 inhibitor. In some embodiments, the Fen1 inhibitor i pharmaceutically acceptable salt thereof.. In some embodiments, the method includes the step of administering the Topi inhibitor. In some embodiments, the Topi inhibitor is irinotecan, topotecan, camptothecin, lamellarin D, or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the method includes the step of administering the Rrm1 inhibitor. In some embodiments, the method includes the step of administering the Rrm2 inhibitor. In some embodiments, the Rrm2 inhibitor is motexafin gadolinium, hydroxyurea, fludarabine, cladribine, tezacitabine, triapine, or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the method includes the step of administering the Aurkb inhibitor. In some embodiments, the Aurkb inhibitor is MK-0457, AZD1152, PHA739358, AT9283, AMG900, SNS-314, TAK- 901 , CYC116, GSK1070916, PF03814735, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the method includes the step of administering the Top2A inhibitor. In some embodiments, the Top2A inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, or a pharmaceutically acceptable salt thereof.

[0046] In some preferred embodiments, the method includes the step of administering an Atr inhibitor.

[0047] In another aspect, the disclosure provides a method for treating cancer in a subject in need thereof, wherein the method includes the step of administering to the subject a therapeutically effective amount of (i) a Myt1 inhibitor, or a pharmaceutically acceptable salt, and (i) a Atr inhibitor, or a pharmaceutically acceptable salt, wherein the cancer comprises a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c- MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV, each in an amount that together is effective to treat the cancer.

[0048] In some embodiments, the method includes the step of administering a therapeutically effective amount of a Myt1 inhibitor, or a pharmaceutically acceptable salt, and a Atr inhibitor, or a pharmaceutically acceptable salt, wherein the cancer comprises a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c- MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

[0049] In some embodiments, the method includes the step of administering a therapeutically effective amount of a Myt1 inhibitor, or a pharmaceutically acceptable salt, and a Atr inhibitor, or a pharmaceutically acceptable salt, wherein the cancer is previously identified as a cancer comprising a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

[0050] In some particular embodiments, the Atr inhibitor is a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the Atr inhibitor is a compound of formula (IV): (IV), or a pharmaceutically acceptable salt thereof, wherein is a double bond, and each W is independently N or CR12; or is a single bond, and each W is independently NRW, carbonyl, or C(RW)2; wherein each RWis independently H or optionally substituted C1-6alkyl; R9is optionally substituted C1-6alkyl or H; R10is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-9heterocyclyl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, halogen, –N(R13)2, –OR13, –CON(R14)2, –SO2N(R14)2,–SO2R13A, or –U–R13B; R11is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R12is independently hydrogen, halogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl; each R13is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or –SO2R13A; or both R13, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R13Ais independently optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, or optionally substituted C6-10 aryl; R13Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9heteroaryl, –N(R13)2, –CON(R14)2, –SO2N(R14)2, –SO2R13A, or optionally substituted alkoxy; each R14is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8cycloalkyl, or optionally substituted C1-9heteroaryl; or both R14, together with the atom to which they are attached, combine to form an optionally substituted C2-9heterocyclyl; U is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; and V is hydrogen or halogen. In some embodiments, the Atr inhibitor is a compound of formula (V): or a pharmaceutically acceptable salt thereof, wherein each W is independently N or CR12; R9is optionally substituted C1-6alkyl or H; R10is optionally substituted C2-9heterocyclyl, optionally substituted C1-6alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, halogen, –N(R13)2, –OR13, –CON(R14)2, –SO2N(R14)2,–SO2R13A, or –U–R13B; R11is optionally substituted C1-9heteroaryl or optionally substituted C1-9heteroaryl C1-6alkyl; each R12is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl; each R13is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9heteroaryl, or –SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R13Ais independently optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, or optionally substituted C6-10aryl; R13Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, –N(R13)2, –CON(R14)2, –SO2N(R14)2, –SO2R13A, or optionally substituted alkoxy; each R14is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9heterocyclyl; U is optionally substituted C2-9heterocyclylene, optionally substituted C3-8cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; and V is hydrogen or halogen. In some embodiments, the Atr inhibitor is selected from the group consisting of compounds A43, A57, A62, A87, A93, A94, A95, A99, A100, A106, A107, A108, A109, A111, A112, A113, A114, A115, A116, A118, A119, A120, A121 (camonsertib), A122, A123, A135, A147, A148, and pharmaceutically acceptable salts thereof. In some embodiments, the Atr inhibitor is compound A43 or a pharmaceutically acceptable salt thereof. In some embodiments, the Atr inhibitor is camonsertib or a pharmaceutically acceptable salt thereof. In some embodiments, the Atr inhibitor is compound A122 or a pharmaceutically acceptable salt thereof. In some embodiments, the Atr inhibitor is elimusertib (BAY1895344) ceralasertib (AZD6738) berzosertib (VE-822)

[0052] SKLB-197 or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the method includes the step of administering a Ttk inhibitor. In some embodiments, the Ttk inhibitor is BAY1217389 or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes the step of administering a Sod1 inhibitor. In some embodiments, the Sod1 inhibitor is LCS1 , ATN-224, Pyrimethamine, a compound of the following structure or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes the step of administering a Sod2 inhibitor. In some embodiments, the Sod2 inhibitor is LCS1 , ATN-224, pyrimethamine, or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the method includes the step of administering a Bub1 inhibitor. In some embodiments, the Bub1 inhibitor is BAY-320, BAY-419, BAY1816032, or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the method includes the step of administering a Cdc7 inhibitor. In some embodiments, the Cdc7 inhibitor is SRA141 , TAK931 , or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the method includes the step of administering a Sae1 inhibitor. In some embodiments, the Sae1 inhibitor is ML792 or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the method includes the step of administering a Plk1 inhibitor. In some embodiments, the Plk1 inhibitor is BI2536, BI6727, TAK960, NMSP937, GSK461364, or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the method includes the step of administering a Uba2 inhibitor. In some embodiments, the Uba2 inhibitor is TAK981 or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the method includes the step of administering a Dut inhibitor. In some embodiments, the Dut inhibitor is TAS114 or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the method includes the step of administering a Hdac3 inhibitor. In some embodiments, the Hdac3 inhibitor is RGFP966 or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the method includes the step of administering a Chekl inhibitor. In some embodiments, the Chekl inhibitor is SRA737 or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the method includes the step of administering an Aurka inhibitor. In some embodiments, the Aurka inhibitor is MLN8237, MK-0457, MLN8054, PHA739358, AT9283, AMG900, MK5108, SNS314, TAK901 , CYC116, ENMD2076, or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the method includes the step of administering a Men1 inhibitor. In some embodiments, the Men1 inhibitor is MI3454, SNDX5613, VTP50469, KO539, or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the method includes the step of administering a Doti I inhibitor. In some embodiments, the Doti I inhibitor is EPZ5676 or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the method includes the step of administering a Crebbp inhibitor. In some embodiments, the Crebbp inhibitor is CPI4, CCS1477, E7386, NEO1132, NEO2734, PRI724, C82, BC001 , C646, EML425, CBP30, or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the method includes the step of administering an Ezh2 inhibitor. In some embodiments, the Ezh2 inhibitor is EPZ-6438, GSK126, or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the method includes the step of administering a Plk4 inhibitor. In some embodiments the Plk4 inhibitor is a compound of formula (VI) , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; L is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted C6-10 aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of RL; R15Ais hydrogen, halogen, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or nitrile; R15Bis hydrogen; or R15Aand R15B, together with the atoms to which they are attached, are C2-9heterocyclyl, C6-10aryl, or C1-9 heteroaryl; A is O or S, and RA’and RA”are both absent; or A is N, RA’is absent, and RA”is hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl, or R2Band L, together with the atom to which they are attached, combine to form an optionally substituted C2-9heterocyclyl or optionally substituted C2-9heteroaryl; or A is C, and each of RA’and RA”are independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, or optionally substituted C1-6alkylsulfonyl; each RLis independently halogen, cyano, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, -S(O)mRLA, -N(RLB)2, or -ORLB; RLAis optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, -ORLBor -N(RLB)2.each RLBis independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, or optionally substituted C1-6alkylsulfonyl; or two RLBgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9heterocyclyl; J is N, and R16is absent; or J is C, and R16is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, or optionally substituted C1-9 heteroaryl; R17is optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9 heteroaryl, -CONH2, or -E-R17A; E is optionally substituted amino, optionally substituted C2-9heterocyclylene, optionally substituted C2-9heteroarylene, optionally substituted C6-10arylene, or optionally substituted C3-8cycloalkylene; R17Ais hydrogen, halogen, cyano, optionally substituted C1-6 alkylsulfonyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, or optionally substituted C1-9heteroaryl; R18is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or -OR18A; and R18Ais hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, or optionally substituted C3-8cycloalkyl. In some embodiments, the Plk4 inhibitor is a compound of formula (VII) . or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; L is optionally substituted C2-9heterocyclyl, optionally substituted C2-9heteroaryl, optionally substituted C6-10 aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of RL; R15Ais hydrogen, halogen, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, or nitrile; R15Bis hydrogen; or R15Aand R15B, together with the atoms to which they are attached, are C2-9heterocyclyl, C6-10aryl, or C1-9heteroaryl; A is O or S, and RA’and RA”are both absent; or A is N, RA’is absent, and RA”is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, or optionally substituted C1-6alkylsulfonyl, or RA”and L, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl or optionally substituted C2-9 heteroaryl; or A is C, and each of RA’and RA”are independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; each RLis independently halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, -S(O)mRLA, -N(RLB)2, or -ORLB; RLAis optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -ORLBor -N(RLB)2. each RLBis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, or optionally substituted C1-6 alkylsulfonyl; or two RLBgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl; R17is optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -CONH2, or -E-R17A; E is optionally substituted amino, optionally substituted C2-9heterocyclylene, optionally substituted C2-9heteroarylene, optionally substituted C6-10arylene, or optionally substituted C3-8cycloalkylene; R17Ais hydrogen, halogen, cyano, optionally substituted C1-6 alkylsulfonyl, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl; R18is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, or -OR18A; and R18Ais hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, or optionally substituted C3-8cycloalkyl. In some embodiments, the Plk4 inhibitor is a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; L is optionally substituted C2-9heterocyclyl, optionally substituted C2-9heteroaryl, optionally substituted C6-10aryl, or optionally substituted C3-8cycloalkyl, wherein L is further optionally substituted by n occurrences of RL; R15Ais hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, or nitrile; R15Bis hydrogen; or R15Aand R15B, together with the atoms to which they are attached, are C2-9 heterocyclyl, C6-10 aryl, or C1-9heteroaryl; ; A is O or S, and RA’and RA”are both absent; or A is N, RA’is absent, and RA”is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, or optionally substituted C1-6alkylsulfonyl, or RA”and L, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl or optionally substituted C2-9 heteroaryl; or A is C, and each of RA’and RA”are independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; each RLis independently halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, -S(O)mRLA, -N(RLB)2, or -ORLB; RLAis optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, -ORLBor -N(RLB)2.each RLBis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, or optionally substituted C1-6alkylsulfonyl; or two RLBgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl; R16is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9heteroaryl; R17is optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -CONH2, or -E-R17A; E is optionally substituted amino, optionally substituted C2-9heterocyclylene, optionally substituted C2-9heteroarylene, optionally substituted C6-10arylene, or optionally substituted C3-8cycloalkylene; R17Ais hydrogen, halogen, cyano, optionally substituted C1-6 alkylsulfonyl, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl; R18is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, or -OR6A; and R18Ais hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, or optionally substituted C3-8 cycloalkyl. In some embodiments, the Plk4 inhibitor is selected from the group consisting of compound P1 to P328. In some embodiments, the Plk4 inhibitor is selected from the group consisting of compounds P16, P17, P25, P44, P45, P62, P110, P121, P137, P140, P151, P156, P164, P174, P179, P182, P183, P188, P195, P196, P197, P210, P189, P232, P238, P240, 243, P249, P252, 255, P260, P262, P272, P273, P274, P276, P277, P280, P308, P328, P334, P340, P343, P347, P348, P349, P350, P351, P352, P353, P354, P355, P356, P357, P358, P359, P360, P361, P362, P363, and P364. In some embodiments the Plk4 inhibitor is centrinone, CFI400945, or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes the step of administering the Haspin inhibitor. In some embodiments, the Haspin inhibitor is SEL120 or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes the step of administering the Mettl3 inhibitor. In some embodiments, the Mettl3 inhibitor is UZH1a, sTC-15, or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes the step of administering the nucleoside analog. In some embodiments, the nucleoside analog is cytarabine, gemcitabine, mercaptopurine, azacytidine, cladribine, decitabine, fluorouracil, floxuridine, fludarabine, nelarabine, or a pharmaceutically acceptable salt thereof or a combination thereof. In some embodiments, the nucleoside analog is gemcitabine or a pharmaceutically acceptable salt thereof. In some embodiments, the nucleoside analog is fluorouracil or a pharmaceutically acceptable salt thereof. In some embodiments, the nucleoside analog is a combination of gemcitabine or a pharmaceutically acceptable salt thereof and fluorouracil or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the method includes the step of administering the platinum-based DNA damaging agent. In some embodiments, the platinum-based DNA damaging agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin. In some embodiments, the platinum-based DNA damaging agent is carboplatin.

[0069] In some embodiments, the Wee1 inhibitor, Fen1 inhibitor, Topi inhibitor, Rrm1 inhibitor, Rrm2 inhibitor, Aurkb inhibitor, Top2A inhibitor, Atr inhibitor, Ttk inhibitor, Sod1 inhibitor, Sod2 inhibitor, Bub1 inhibitor, Cdc7 inhibitor, Sae1 inhibitor, Plk1 inhibitor, Uba2 inhibitor, Dut inhibitor, Hdac3 inhibitor, Chekl inhibitor, Aurka inhibitor, Men1 inhibitor, Doti I inhibitor, Crebbp inhibitor, Ezh2 inhibitor, Plk4 inhibitor, Haspin inhibitor, Mettl3 inhibitor, nucleoside analog, platinum-based DNA damaging agent, or the combination thereof is administered as a pharmaceutical composition.

[0070] Definitions

[0071] The term "aberrant," as used herein, refers to different from normal. When used to describe 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.

[0072] The term “acyl,” as used herein, represents a group -C(=O)-R, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl. Acyl may be optionally substituted as described herein for each respective R group.

[0073] 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 colorectal cancer.

[0074] 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 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.

[0075] 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.

[0076] 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 alkenyl.

[0077] 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 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.

[0078] 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.

[0079] 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, 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; -C(O)R or -SC>2R, where R is amino; and =NR’, where R’ is H, alkyl, 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.

[0080] 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.

[0081] The term “alkylamino,” as used herein, refers to a group having the formula -N(RN1)2 or -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.

[0082] The term “alkylsulfenyl,” as used herein, represents a group of formula —S— (alkyl). Alkylsulfenyl may be optionally substituted as defined for alkyl.

[0083] The term “alkylsulfinyl,” as used herein, represents a group of formula -S(O)-(alkyl). Alkylsulfinyl may be optionally substituted as defined for alkyl.

[0084] The term “alkylsulfonyl,” as used herein, represents a group of formula -S(O)2-(alkyl). Alkylsulfonyl may be optionally substituted as defined for alkyl.

[0085] The term “alkynyl,” as used herein, represents monovalent straight or branched chain 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 “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 alkynyl.

[0086] The term “amino,” as used herein, represents -N(RN1)2, where, if amino is unsubstituted, both RN1are H; or, if amino is substituted, each RN1is independently H, -OH, -NO2, -N(RN2)2, -SO2ORN2, -SO2RN2, - SORN2, -C(O)ORN2, 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 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 group is -NHRN1, in which RN1is optionally substituted alkyl.

[0087] 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, fluorenyl, indanyl, indenyl, etc. The aryl 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; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silyl; -(CH2)n- C(O)ORA; -C(O)R; and -SO2R, where R is amino or alkyl, RAis H or alkyl, and n is 0 or 1 . Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group.

[0088] 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.

[0089] The term “arylene,” as used herein, refers to a divalent aryl group. An optionally substituted arylene is an arylene that is optionally substituted as described herein for aryl.

[0090] 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.

[0091] The term “azido,” as used herein, represents an -N3 group.

[0092] The term "cancer," as used herein, refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans).

[0093] 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, are formed by carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloalkynyl, and certain aryl groups.

[0094] The term “carbonyl,” as used herein, represents a -C(O)- group.

[0095] 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. The terms “CCNE1 ” and “cyclin E1 as used interchangeably herein, refer to G1 / S specific cyclin E1 (encoded for by the CCNE1 gene). A cell overexpressing CCNE1 (alternatively referred to herein as a CCNE1-high cell) is one that exhibits a higher activity of CCNE1 than a cell normally expressing CCNE1. For example, a CC / VE7-overexpressing cell is a cell that exhibits a copy number of at least 3 compared to a diploid normal cell with 2 copies. Thus, a cell exhibiting a copy number greater than 3 of CCNE1 is a cell overexpressing CCNE1. The CCNE1 overexpression may be measured by identifying the expression level of the gene product in a cell (e.g., CCNE1 mRNA transcript count or CCNEI protein level).

[0096] The term “Cdc25A” as used herein, refers to M-phase inducer phosphatase 1 (encoded for by the CDC25A gene). Cdc25A acts to prevent the inhibition of Cdk proteins by removing inhibitory phosphorylation events. A CDC25A gene with a gain-of function mutation is one which encodes for a Cdc25A protein which increased activity, e.g., one with more activity for dephosphorylating Cdk proteins.

[0097] The term “Cdk” as used herein, refers to the family of cyclin-dependent kinases, e.g., cyclin- dependent kinase 4 (Cdk4; encoded for by the CDK4 gene), cyclin-dependent kinase 6 (Cdk6, encoded for by the CDK6 gene), or cyclin-dependent kinase 12 (Cdk12; encoded for by the CDK12 gene). Cdk proteins interact with a variety of regulatory proteins via phosphorylation of prescribed sites of the protein, either activating or inhibiting the protein. Though they are most commonly associated with cyclin proteins (e.g., cyclin A, cyclin B, cyclin C, cyclin D, cyclin E, cyclin F, cyclin G, cyclin H, cyclin I, cyclin J, cyclin K, cyclin L, cyclin O, cyclin P, cyclin T, and cyclin Y), Cdk proteins are known to interact with and regulate several other cell-signaling proteins. A CDK gene with a loss-of-fu notion mutation is one that fails to produce a functional Cdk protein or produces reduced quantities of Cdk protein in a cell.

[0098] The term “CDKN2A" as used herein refers to the CDKN2A gene, which encodes for the p16 and p14arf proteins. Both p16 and P14arf are inhibitors of Cdk proteins, such as Cdk4 and Cdk6. A mutation to CDKN2A (e.g., a loss of function mutation) may result in a p16 or p14arf protein with reduced functionality. Accordingly, they may fail to inhibit the activity of Cdk proteins, increasing the relative activity of the Cdk protein.

[0099] The term “cyano,” as used herein, represents -CN group.

[0100] 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, 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.

[0101] 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 the individual groups defined herein.

[0102] The term “cycloalkenylene,” as used herein, represents a divalent cycloalkenyl group. An optionally substituted cycloalkenylene is a cycloalkenylene that is optionally substituted as described herein for cycloalkyl.

[0103] 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 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.O]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 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., 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 Jheptyl, 2-bicyclo[2.2.1 Jheptyl, 5-bicyclo[2.2.1 Jheptyl, 7-bicyclo[2.2.1 Jheptyl, and decalinyl. The cycloalkyl group may be unsubstituted 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 optionally substituted amino; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl; and -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.

[0104] 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 substituted as the individual groups described herein.

[0105] 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.

[0106] 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 cycloalkyl.

[0107] "Disease" or "condition" refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.

[0108] The term “EGFR,” as used herein, refers to the epidermal growth factor receptor protein (encoded for by the EGFR gene). EGFR is a transmembrane glycoprotein with an extracellular domain and an intracellular domain. The extracellular domain receives signals (e.g., in the form of a signal peptide such as epidermal growth factor), resulting in a confirmational or chemical change in the intracellular domain. The intracellular domain may then interact with a variety of cell signaling pathways (e.g., the RAS / MAPK pathway). An EGFR gene with a loss-of-function mutation is one that fails to produce a functional EGFR protein or produces reduced quantities of EGFR protein in a cell.

[0109] The term “FBXW7,” as used herein, refers to F-box / WD Repeat-Containing Protein 7 transcript (gene name: FBXW7). An FBXW7 gene having an inactivating mutation is one that fails to produce a functional FBXW7 protein or produces reduced quantities of FBXW7 protein in a cell. The terms “guanidine triphosphatases” or“GTPase,” as used herein, refer to enzymes which dephosphorylate guanidine triphosphate (GTP) into guanidine diphosphate (GDP).

[0110] The term “halo,” as used herein, represents a halogen selected from bromine, chlorine, iodine, and fluorine.

[0111] 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, 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, -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 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.

[0112] The term “heteroaryl alkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group, each as defined herein. The heteroaryl and alkyl portions may be optionally substituted as the individual groups described herein.

[0113] 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.

[0114] 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.

[0115] 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 from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, “heterocyclyl” is a 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. Heterocyclyl can be aromatic or non-aromatic. Nonaromatic 5-membered heterocyclyl has zero or 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, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, etc. 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 examples of heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl (e.g., 1 ,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, etc. The term “heterocyclyl” also 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, 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; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silyl; cyano; -C(O)R or -SC>2R, where R is amino or alkyl; =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.

[0116] 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.

[0117] 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.

[0118] The term “(heterocyclyl)oxy,” as used herein, represents a chemical substituent of formula -OR, where R is a heterocyclyl group, unless otherwise specified. (Heterocyclyl)oxy can be optionally substituted in a manner described for heterocyclyl.

[0119] 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 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 greater (e.g., at least 4750 times greater, e.g., up to 5000 times greater) than the natural abundance of deuterium.

[0120] The term “HPV,” as used herein, refers to the human papillomavirus. A subject infected with HPV (e.g., a subject currently possessing a viral load of HPV) may incur long term DNA damage, which in turn may result in the development of a cancer (e.g., a cancer described herein). DNA damage sustained from HPV may remain in a subject long after the subject is cured of HPV (e.g., a subject wherein the HPV viral load is reduced, a subject wherein the HPV viral load is reduced to zero, a subject with reduced or eliminated disease symptoms from a HPV infection, etc.). A subject currently or formerly infected with HPV may be referred to as “HPV+” herein.

[0121] The term “Hras” (or alternatively “H-Ras,” or “H-ras”), as used herein, refers to a protein, peptide, or polypeptide encoded for by the HRAS (or alternatively “H-RAS") gene. “HRAS mutation,” as used herein, refers to a mutation in the HRAS gene which results in the alteration of the amino acid sequence of an Hras protein. HRAS mutations are commonly observed in thyroid cancer, bladder cancer, head and neck cancer, and kidney cancer.

[0122] The term “Kras” (or alternatively “K-Ras,” or “K-ras”), as used herein, refers to a protein, peptide, or polypeptide encoded for by the KRAS (or alternatively “K-RAS") gene. Two common isoforms of the Kras protein are known, isoform a (Kras4A) and isoform b (Kras4B), which arise from alternative gene splicing. Unless otherwise specified, Kras should be understood to refer to both isoforms. “KRAS mutation,” as used herein, refers to a mutation in the KRAS gene which results in the alteration of the amino acid sequence of a Kras protein. KRAS mutations are commonly observed in colorectal cancer, lung cancer, pancreatic cancer, gynecological cancer (e.g., uterine cancer, ovarian cancer, cervical cancer, etc.) and gastro-esophageal cancer.

[0123] 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 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).

[0124] The term “lymphoma,” as used herein, refers to a cancer arising from cells of immune origin.

[0125] The term "melanoma," as used herein, is taken to mean a tumor arising from the melanocytic system of the skin and other organs.

[0126] The term “Myc” as used herein, refers to the Myc family of cell signaling proteins. The MYC family includes c-Myc, l-Myc, and n-Myc (encoded for by the c-MYC, l-MYC, and n-MYC genes respectively; collectively referred to as MYC genes). Myc family proteins perform several regulatory processes across cellular functions, many of which are associated with cell division, cell proliferation, and DNA replication. A c-MYC gene with a gain-of-function mutation is one that produces a c-Myc protein with enhanced activity (e.g., a c-Myc protein which participates in a signal transduction pathway in the absence of a signal activating the pathway) or produces increased quantities of a c-Myc protein in a cell. A cell overexpressing c-MYC is one that exhibits a higher activity of a c-MYC gene than a cell normally expressing c-MYC. For example, a c-MYC-overexpressing cell is a cell that exhibits a copy number of at least 3 compared to a diploid normal cell with 2 copies. Thus, a cell exhibiting a copy number greater than 3 of c-MYC is a cell overexpressing c-MYC. c-MYC overexpression or c-MYC amplification may be measured by identifying the expression level of the gene product in a cell (e.g., MYC mRNA transcript count or MYC protein level).

[0127] The term “Myt1 ,” as used herein, refers to membrane-associated tyrosine and threonine-specific CDC2-inhibitory kinase (Myt1) (Gene name PKMYT1). The term “Myt1 inhibitor,” as used herein, represents 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 the measured Myt1 IC50 is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain Myt1 inhibitors, the Myt1 IC50 may be 100 nM or less (e.g., 10 nM or less, or 3 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the Myt1 IC50 is 1 nM to 1 pM (e.g., 1 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM). Even more preferably, the Myt1 IC50 is less than 20 nm (e.g., 1 nM to 20 nM).

[0128] The term “nitro,” as used herein, represents an -NO2 group.

[0129] The term “Nras” (or alternatively “N-ras” or “N-Ras”), as used herein, refers to a protein, peptide, or polypeptide encoded for by the NRAS (or alternatively “N-RAS") gene. “NRAS mutation,” as used herein, refers to a change to the NRAS gene which results in the alteration of the amino acid sequence of an NRAS protein. NRAS mutations are commonly found in colorectal cancer, thyroid cancer and melanoma.

[0130] The term “oxo,” as used herein, represents a divalent oxygen atom (e.g., the structure of oxo may be shown as =O).

[0131] The term “Ph,” as used herein, represents phenyl.

[0132] 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 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.

[0133] 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, dis integrants, dyes (colors), 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, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, 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, vitamin E, vitamin C, and xylitol.

[0134] 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 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, 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, 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, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0135] The term “Pik3ca,” as used herein, refers to phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (alternatively referred to as P110a; encoded for by the PIK3CA gene); the catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase (Pi3k). Pi3k plays an important role in cell signaling, e.g., the Pi3k / Akt / mtor pathway. A PIKC3A gene with a gain-of-function mutation is one that produces a Pik3ca protein with enhanced activity (e.g., a Pik3ca protein which participates in a signal transduction pathway in the absence of a signal activating the pathway) or produces increased quantities of a Pik3ca protein in a cell.

[0136] The term “Ppp2r1a,” as used herein, refers to the Serine / threonine-protein phosphatase 2A 65kDa regulatory subunit A alpha isoform (encoded by the PPP2R1A gene). Ppp2r1a is a regulatory subunit of protein phosphatase 2 (Pp2a), one of the four major Ser / Thr phosphatases. Wild type Pp2a is implicated for its role in regulating tumor production by controlling phosphorylation events in cell signaling pathways. A PPP2R1A gene with a loss-of-function mutation is one that fails to produce a functional Ppp2r1a protein or produces reduced quantities of Ppp2r1a protein in a cell.

[0137] The term “Pten,” as used herein, refers to the phosphatase and tensin homolog protein (encoded for by the PTEN gene). Pten is a cell-cycle regulating phosphatase that plays a role in the regulation of several cell signaling pathways, e.g., the Akt / Pkb signaling pathway. A PTEN gene with a loss-of-function mutation is one that fails to produce a functional Pten protein or produces reduced quantities of Pten protein in a cell.

[0138] The term “pre-malignant” or “pre-cancerous,” as used herein, refers to a condition that is not malignant but is poised to become malignant.

[0139] 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 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, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4'- dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylpehenoxyacetyl, dimethylformamidino, and 4- nitrobenzoyl.

[0140] Exemplary O-protecting groups for protecting carbonyl containing groups include, but are not limited to: acetals, acylals, 1 ,3-dithianes, 1 ,3-dioxanes, 1 ,3-dioxolanes, and 1 ,3-dithiolanes.

[0141] 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-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).

[0142] 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- dimethoxybenzyloxycarbonyl, 3,5 dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4 methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5 trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methylethoxycarbonyl, a,a-dimethyl-3,5 dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, 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 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).

[0143] The term “Raf (or alternatively, “rapidly accelerated fibrosarcoma”), as used herein, refers to the Raf family of cell signaling proteins. The Raf family of proteins includes Araf, Braf, and CRaf (encoded for by the ARAF, BRAF, and CRAF gene respectively). A BRAF gene with a gain-of-function mutation is one that produces a Braf protein with enhanced activity (e.g., a Raf protein which participates in a signal transduction pathway in the absence of a signal activating the pathway) or produces increased quantities of a BRAF protein in a cell. The term “Ras” (or alternatively “Ras GTPase”), as used herein, refers to the Ras family of cell signaling proteins. The Ras family includes Kras, Hras, and Nras (encoded for by the KRAS, HRAS, and NRAS genes; collectively referred to as RAS genes). About 25% of human cancers are observed to involve a mutation to a RAS gene.

[0144] The term “Ras / Mapk pathway” (or alternatively “Mapk / Erk pathway,” or “Ras-Raf-Mek-Erk pathway”), as used herein, refers to the chain of proteins, typically located in the membrane of the cell, which aids in transducing extracellular signals into the nucleus. The proteins communicate via exchange of groups both between each other and nucleotides. For example, the signaling pathway may be activated by binding phosphorylating a diphosphate nucleoside (e.g., phosphorylating a GDP molecule) or dephosphorylating a triphosphate nucleoside (e.g., dephosphorylating GTP); or the signaling pathway may transduce a signal by interacting a phosphorylated first protein with a second protein, transferring the phosphate from the first protein to the second protein, resulting in a dephosphorylated first protein and a phosphorylated second protein.

[0145] The term “replication stress” as used herein, refers to a cell undergoing more rapid and / or uncontrolled cell division. Many cancers can be characterized as including a biomarker for replication stress, e.g., a mutation (e.g., a loss-of-function mutation or a gain-of-function mutation) of a gene, overexpression of a gene, or amplification of a gene which results in shortening the time a cell spends in the G1 , S, or G2 phases of the cell cycle). Additionally, a therapeutic (e.g., chemotherapeutic) drug may also be a driver of replication stress. Methods of the present disclosure may include administration of one or more therapeutic agents which cause replication stress (e.g., a Myt inhibitor) to a cancer with a replication stress mutation.

[0146] 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 or homogeneous substance.

[0147] The term “subject,” as used herein, represents a human or non-human animal (e.g., a 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.

[0148] 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 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.

[0149] “Treatment” and "treating," as used herein, refer to the medical management of a subject with 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 condition); and supportive treatment (treatment employed to supplement another therapy). BRIEF DESCRIPTION OF THE DRAWINGS

[0150] FIG. 1 A is a plot showing the dose response of a cell including a Kras mutation (Q61 H B4) versus wild-type Kras. The IC50 for treating the mutated Kras is nearly an order of magnitude lower than the IC50 for the wild type Kras (0.093 pM vs. 0.84 pM).

[0151] FIG. 1 B is a plot showing the dose response of a cell including a Kras mutation (G12C E12) versus wild-type Kras. The IC50 for treating the mutated Kras is nearly an order of magnitude lower than the IC50 for the wild type Kras (0.13 pM vs. 1.2 pM).

[0152] FIG. 2A is a plot showing the efficacy of the combination treatment of a cell including a wild-type Kras protein with compound 182 and gemcitabine. In a cancer without a Kras mutation, minimal lethality is observed from both compound 182 and gemcitabine when administered separately. No significant increased lethality observed from the combination.

[0153] FIG. 2B is a plot showing the efficacy of the combination treatment of a cell including a wild-type Kras protein with compound 182 and gemcitabine. In a cancer with a Q61 H Kras mutation, minimal lethality is observed from both compound 182 and gemcitabine when administered separately. When administered in combination, a significant decrease in cell viability is observed.

[0154] FIG. 2C is a plot showing the efficacy of the combination treatment of a cell including a wild-type Kras protein with compound 182 and gemcitabine. In a cancer with a G12C Kras mutation, minimal lethality is observed from both compound 182 and gemcitabine when administered separately. When administered in combination, a significant decrease in cell viability is observed.

[0155] FIG. 3A shows the reduction of tumor growth in a PA1332 pancreatic PDX model when treated with compound 182 and gemcitabine. In the absence of an API, the tumor grows unrestricted. Additionally, when gemcitabine or compound 182 are administered as a monotherapy, the speed of tumor growth is reduced, though tumor growth is still observed. Finally, when administered as a combination therapy, tumor growth is prevented, with the average tumor size decreasing over time. The dotted vertical line denotes when administration of the API was halted.

[0156] FIG. 3B shows the reduction of tumor growth in a PA1194 pancreatic PDX model when treated with compound 182 and gemcitabine. In the absence of an API, the tumor grows unrestricted. Additionally, when gemcitabine or compound 182 are administered as a monotherapy, the speed of tumor growth is reduced, though tumor growth is still observed. Finally, when administered as a combination therapy, tumor growth is prevented, with the average tumor size decreasing over time. The dotted vertical line denotes when administration of the API was halted.

[0157] FIG. 3C shows the reduction of tumor growth in a PA6427 pancreatic PDX model when treated with compound 182 and gemcitabine. In the absence of an API, the tumor grows unrestricted. Additionally, when gemcitabine or compound 182 are administered as a monotherapy, the speed of tumor growth is reduced, though tumor growth is still observed. Finally, when administered as a combination therapy, tumor growth is prevented, with the average tumor size decreasing over time.

[0158] FIG. 4A shows the resulting reduction of tumor volume in a CR3262 colorectal PDX model including a G12D Kras mutation when treated with compound 182 and camonsertib. When administered as a monotherapy or in combination, no significant reduction in tumor growth is observed.

[0159] FIG. 4B shows the resulting reduction of tumor volume in a CR3150 colorectal PDX model including a G12V Kras mutation when treated with compound 182 and camonsertib. When administered as a monotherapy, no significant reduction in tumor growth is observed for either compound 182 or camonsertib. However, when administered as a combination therapy (compound 182 administered at 5 mg / kg twice a day), a significant reduction in tumor volume change overtime is observed.

[0160] FIG. 4C shows the resulting reduction of tumor volume in a CR3099 colorectal PDX model including a G12D Kras mutation when treated with compound 182 and camonsertib. When administered as a monotherapy, a slight reduction in tumor growth is observed for either compound 182 or camonsertib. However, when administered as a combination therapy (compound 182 administered at 5 mg / kg twice a day), a significant reduction in tumor volume change overtime is observed.

[0161] FIG. 4D shows the resulting reduction of tumor volume in a CR3820 colorectal PDX model including a G12D Kras mutation when treated with compound 182 and camonsertib. When administered as a monotherapy, no significant reduction in tumor growth is observed for either compound 182 or camonsertib. However, when administered as a combination therapy (compound 182 administered at 5 mg / kg twice a day), a significant reduction in tumor volume change overtime is observed.

[0162] DETAILED DESCRIPTION

[0163] In general, the present disclosure demonstrates the unexpected efficacy of cancer treatments including multiple sources of replication stress. In particular, the present disclosure relates to the combination of one or more replication stress biomarkers (e.g., a mutation or gene amplification of a gene associated with replication stress, e.g., a mutation or gene amplification of KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, a prior or current infection with HPV, or a combination thereof) and one or more therapeutic agents that exacerbate replication stress or prevent cellular recovery from replication stress (e.g., a Myt1 inhibitor, alone and in combination with a second therapeutic agent). The disclosure further highlights methods of using Myt1 inhibitors for the treatment of cancers with a replication stress biomarker, alone and in combination with a second therapeutic agent.

[0164] Cancer is commonly associated with some form of replication stress - a decrease in control over cell division. Many cancers include a mutated protein associated with a cellular signaling pathway (e.g., a cell-cycle signaling pathway), resulting in decreased regulation of cell division, frequently resulting in the growth of tumors. Several replication stress mutations to a genome can result in a loss of control over cell division (e.g., mutations to any gene encoding a protein which helps regulate cell division). A cell exhibiting a high level of replication stress, may be identified by one or more replication stress biomarkers (e.g., a mutation or gene amplification of KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, a prior or current infection with HPV, or a combination thereof).

[0165] A cancer may be considered a cancer exhibiting a high level of replication stress if it includes one or more replication stress biomarkers (e.g., a mutation or gene amplification of KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, a prior or current infection with HPV, or a combination thereof).

[0166] One method for targeting cancers with replication stress mutations is to administer one or more therapeutic agents which exacerbate the uncontrolled cell division. By placing the cancer cells under increased replication stress or by preventing the recovery from said replication stress, the viability of the daughter cancer cells decreases through the induction of, e.g., DNA breaks and chromosome pulverization as cells fail to complete DNA replication or chromosome segregation before the next mitotic event. Membrane-associated tyrosine and threonine-specific cdc2-inhibatory kinase (Myt1) inhibitors may serve as one such therapeutic agent.

[0167] Myt1 inhibitors may be used to inhibit Myt1 in a cell, e.g., a cell in a subject (e.g., a cell under replication stress or a cell with a replication stress biomarker). Myt1 is a cell cycle regulating kinase localized predominantly in the endoplasmic reticulum and Golgi complex. It is part of the Wee family of kinases that includes Wee1 and Weel b. It is involved in the negative regulation of the Cdk1-Cyclin B complex which promotes the progression of cells from G2-phase into the mitotic phase (M-phase) of the cell cycle. During DNA damage, Myt1 drives the phosphorylation on Cdk1 (both Tyr15 and Thr14 of Cdk1) which maintains the kinase complex in an inactive state in G2 as part of the G2 checkpoint response along with Wee1 (which mediates only Tyr15 phosphorylation) and prevents entry into mitosis until the damage has been repaired. Additionally, it has been proposed that Myt1 directly interacts with Cdk1 complexes in the cytoplasm and prevents their nuclear translocation thus inhibiting cell cycle progression.

[0168] Myt1 has been implicated as a potentially important cancer target as it is essential in many cancer cells. Over-expression of Myt1 has been observed in various cancers including hepatocellular carcinoma as well as clear-cell renal-cell carcinoma. Myt1 downregulation has a minor role in unperturbed cells but has a more prominent role in cells exposed to DNA damage. Additionally, cells that exhibit high levels of replication stress may be particularly sensitive to loss of Myt1 function, as these cells will be prone to entering mitosis prematurely with compromised genomic material leading to mitotic catastrophe.

[0169] Myt1 inhibitors (e.g., any of compounds 1 to 326) may be particularly useful in the treatment of tumors harboring a replication stress biomarker (e.g., a mutation or gene amplification of a gene which results in replication stress (e.g., a mutation or gene amplification of KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, a prior or current infection with HPV, or a combination thereof).

[0170] Particular benefit in the treatment of a cancer associated with a replication stress biomarker may be observed in a combination therapy, e.g., a combination therapy between an Myt1 inhibitor and a second chemotherapeutic agent, (e.g., a DNA-synthesis interfering chemotherapy agent, e.g., a nucleoside analog (e.g., gemcitabine) or an Atr inhibitor (e.g., any one of compound A1-A152)). A synergistic effect (e.g., a synthetic lethal effect) may be observed for the combination, wherein the second chemotherapeutic agent (in combination with a replication stress biomarker, e.g., a replication stress biomarker described herein) increases the cell’s dependence on PKMYT1 for controlling mitosis. The Myt1 inhibitor then inhibits PKMYT1 activity, driving premature mitosis and resulting in efficient cell death.

[0171] The second therapeutic agent may be, e.g., a Wee1 inhibitor, Fen1 inhibitor, Topi inhibitor, Rrm1 inhibitor, Rrm2 inhibitor, Aurkb inhibitor, Top2A inhibitor, Atr inhibitor, Ttk inhibitor, Sod1 inhibitor, Sod2 inhibitor, Bub1 inhibitor, Cdc7 inhibitor, Sae1 inhibitor, Plk1 inhibitor, Uba2 inhibitor, Dut inhibitor, Hdac3 inhibitor, Chekl inhibitor, Aurka inhibitor, Men1 inhibitor, Doti I inhibitor, Crebbp inhibitor, Ezh2 inhibitor, Plk4 inhibitor, Haspin inhibitor, Mettl3 inhibitor, nucleoside analog, platinum-based DNA damaging agent, or a combination thereof.

[0172] Replication Stress Biomarkers

[0173] The present disclosure includes methods for the treatment of a cell (e.g., a cell in a tumor or a cell in a subject) including a replication stress biomarker. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer includes a replication stress biomarker. In some embodiments, the cancer is associated with or characterized by a replication stress biomarker. In some embodiments, the cancer has been previously identified as including a replication stress biomarker. In some embodiments, the replication stress biomarker is a mutation to a replication stress associated gene. In some embodiments, the replication stress biomarker is a gain-of-function mutation. In some embodiments, the replication stress biomarker is a loss-of-function mutation. In some embodiments, the replication stress biomarker is overexpression or gene amplification of a replication stress associated gene. In some embodiments, the replication stress biomarker is reduced expression of a replication stress associated gene. In some embodiments, the cancer is characterized by a resistance to an inhibitor of a replication associated protein. In some embodiments, the replication stress biomarker is a mutation or gene amplification to a gene encoding a cell-division-signaling protein. In some embodiments, the replication stress biomarker is a mutation (e.g., a gain-of-function mutation or a loss-of-function mutation), overexpression, or gene amplification of KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, a prior or current infection with HPV, or a combination thereof.

[0174] RAS Biomarkers

[0175] The Ras family of proteins includes 3 closely related proteins: Hras, Kras, and Nras (encoded for by the HRAS gene, the KRAS gene, and the NRAS gene respectively) expressed in mammalian cells. Ras proteins are members of the protein superfamily of small guanidine triphosphatases (GTPases, e.g., Ras, Rho, Ran, Rab, and Arf GTPases). Ras proteins may bind to GTP molecules, converting the RAS protein into an “activated state” (Ras-GTP). The activated Ras-GTP complex may then be dephosphorylated, converting the Ras protein into a “deactivated state” (Ras-GDP). Many cancers are highly associated with mutations to a Ras protein (e.g., uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, thyroid cancer, melanoma, and endometrial cancer). KRAS mutations are particularly common in colorectal cancers, pancreatic cancers, lung cancers, gynecological cancers (e.g., uterine cancers, ovarian cancers, or cervical cancers) and gastroesophageal cancers. For example, reports have shown that more than 90% of pancreatic cancers, 50% of colorectal cancers, and 30% of lung cancers include a KRAS mutation. HRAS mutations are particularly common in thyroid cancers, kidney cancers, bladder cancers, and head and neck cancers. NRAS mutations are particularly common in colorectal cancers and melanomas.

[0176] Ras proteins are critical members of the Ras / Mapk pathway (also referred to as the Ras / Mapk pathway, the Mapk / Erk pathway, or the Ras-Raf-Mek-Erk pathway) and are implicated in a handful of other signaling pathways including the Pi3k / Akt pathway, the Rac / Pak pathway, the RASSF1 / 5 - MST2 pathway, the Rho pathway, Rap1 signaling, and PLCe signaling. The proteins of the Ras / Mapk pathway communicate via exchange of groups (e.g., phosphate groups) both between each other and nucleotides. For example, the signaling pathway may be activated by phosphorylating a diphosphate nucleoside (e.g., phosphorylating a GDP molecule) or dephosphorylating a triphosphate nucleoside (e.g., dephosphorylating GTP); or the signaling pathway may transduce a signal by interacting a phosphorylated first protein with a second protein, transferring the phosphate from the first protein to the second protein, resulting in a dephosphorylated first protein and a phosphorylated second protein. Active Ras-GTP begins the start of a kinase cascade, activating or transducing signals to several cell signaling pathways (e.g., the Ras / Mapk pathway, the Pi3k / Akt pathway, the Rac / Pak pathway, the Rassf1 / 5 - Mst2 pathway, the Rho pathway, Rap1 signaling, and Pice signaling), including pathways responsible for regulating cell division.

[0177] Mutations to any protein in the Ras / Mapk pathway can result in a breakdown of cellular signaling, either preventing the cell from transducing certain signals to the nucleus or stimulating the cell as if an absent signal were present. For example, mutations to a RAS gene (e.g., KRAS) may inhibit the dephosphorylation of the Ras-GTP complex. This results in the prolonged activation of the Ras protein, and therefore prolonged signaling (e.g., signaling to continue cell division). Uncontrolled cell division upon activation of the Ras protein is known to drive replication stress.

[0178] More than 25% of human tumors include a mutated RAS gene. Additionally, several cancers are associated with an increased expression (i.e., gene amplification) of a RAS gene, particularly amplification of KRAS. However, due to many factors such as the structure and high binding affinity of Kras for GTP, KRAS-associated cancers are incredibly difficult to treat via chemotherapy.

[0179] Myt1 inhibitors (e.g., any one of compounds 1 to 328) may serve as particularly potent chemotherapeutic treatments for cancers associated with a RAS mutation (e.g., KRAS-associated cancers, HRAS-associated cancers, or / VRAS-associated cancers). Myt1 inhibitors, as described herein, inhibit the ability of treated cells to recover from replication stress. Therefore, in combination with RAS mutations which induce replication stress, Myt1 inhibitors may drive premature mitosis in affected cells, thereby killing the mutant cells.

[0180] In some embodiments, the RAS mutation is a KRAS mutation. In some embodiments, the KRAS mutation encodes for an amino acid substitution in a Kras protein, wherein the amino acid substitution is G12D, G12V, G12C, G13D, G12R, G12A, Q61 H, G12S, A146T, G13C, Q61 L, Q61 R, K117N, A146V, G12F, Q61 K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof. In some embodiments, the RAS mutation is an HRAS mutation, the HRAS mutation encodes for an amino acid substitution in a Hras protein, wherein the amino acid substitution is Q61 R, G13R, Q61 K, G12S, Q61 L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61 H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof. In some embodiments, the RAS mutation is a NRAS mutation. In some embodiments, the NRAS mutation encodes for an amino acid substitution in a Nras protein, wherein the amino acid substitution is Q61 R, Q61 K, G12D, Q61 L, Q61 H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61 P, A59D, E132K, E49K, T50I, A146V, orA59T, and combinations thereof.

[0181] In some embodiments, the cancer to be treated is a cancers associated with a RAS mutation (e.g., a RAS mutation described above). In some embodiments, the cancer is uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, or endometrial cancer. In embodiments wherein the RAS mutation is a KRAS mutation, the cancer is preferably colorectal cancer, pancreatic cancer, lung cancer, a gynecological cancer (e.g., uterine cancer, ovarian cancer, cervical cancer), or gastro-esophageal cancers. In embodiments wherein the RAS mutation is a HRAS mutation, the cancer is preferably thyroid cancer, kidney cancer, bladder cancer, or a head and neck cancer. In embodiments wherein the RAS mutation is an NRAS mutation, the cancer is preferably a colorectal cancer or a melanoma. In some embodiments, the cancer is associated with RAS amplification. In some embodiments, the cancer is associated with KRAS amplification. TP53 Biomarkers

[0182] Transformation-related protein 53 (alternatively referred to as p53, Tumor Protein P53, cellular tumor antigen p53, or Tp53; encoded by the TP53 gene) is a regulatory protein associated with ensuring healthy cell division by preventing genomic mutation. Tp53 plays a role in activating DNA repair, preventing the transition to the mitotic stage of cell division, and the initiation of apoptosis, in cells with sufficiently damaged DNA. Due to its role in actively repairing DNA, Tp53 is classified as a “tumor suppressor gene,” and is commonly mutated in cancer cells. TP53 mutations are found in from about 30% to about 50% of ovarian cancers, esophageal cancers, colorectal cancers, head and neck cancers, and lung cancers. As a result, mutations to TP53 may be replication stress mutations. Accordingly, cancers harboring a TP53 mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy). In some embodiments, the cancer to be treated by the methods of the present disclosure include a TP53 mutation. In some embodiments, the TP53 mutation encodes for Tp53z-.

[0183] CCNE1 Biomarkers

[0184] Cyclin E1 (encoded by the CCNE1 gene) is involved in the G1 to S phase cell cycle transition. In late G1 phase of the cell cycle, it complexes with cyclin-dependent kinase 2 (Cdk2) to promote E2F transcription factor activation and entry into S-phase. Cyclin E1 levels are tightly regulated during normal cell cycles, accumulating at the G1 / S transition and being completely degraded by the end of S phase. The cell cycle-dependent proteasomal degradation of Cyclin E1 is mediated by the SCFFBW7ubiquitin ligase complex. Once activated in late G1 , the Cyclin E1 / Cdk2 complex promotes the transition into S phase through phosphorylation and inactivation of pRB and subsequent release of E2F transcription factors. S phase is promoted by E2F-mediated transcription of numerous genes involved in DNA replication including the pre-replication complex subunits Orel , Cdc6, Cdt1 , and the Mem helicase factors. CCNE1 is frequently amplified and / or over-expressed in human cancers. CCNE1 amplification has been reported in several cancer types including ovarian cancer, breast cancer, uterine cancer, pancreatic cancer, bladder cancer, gastric cancer, esophageal cancers, and sarcomas.

[0185] CCNE1 over-expression is thought to drive tumorigenesis by inducing genome instability (e.g., increased origin firing, defective nucleotide pools, transcription-replication conflicts, and / or fork instability). Over-expression of CCNE1 has been shown to induce replication stress characterized by slowed or stalled replication forks and loss-of-heterozygosity at fragile sites. The primary mechanism by which CCNE1 over-expression causes replication stress is increased origin firing in early S-phase followed by depletion of replication factors including nucleotide pools. The decrease in overall replication proteins and nucleotides decreases fork progression and causes stalling and subsequent collapse or reversal.

[0186] As a result, CCNE1 amplification is a replication stress biomarker. Accordingly, cancers harboring a CCNE1 mutation, or characterized by CCNE1 over-expression may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0187] In some embodiments, the cancer may include a CCNE1 mutation, overexpression, or amplification. In some embodiments, the cancer includes at least one other replication stress biomarker (e.g., a replication stress biomarker described herein) and a CCNE1 mutation, overexpression, or amplification.

[0188] CDK12 Biomarkers

[0189] Cyclin dependent kinase 12 (Cdk12; encoded for by the CDK12 gene) is a member of the cyclin dependent kinase (Cdk) family of cell-cycle serine-threonine kinases. Cdk family kinases interact with a variety of regulatory proteins via phosphorylation of prescribed sites of the protein, either activating or inhibiting the protein. Cdk proteins play regulatory roles at numerous phases of the cell cycle and the transitions therebetween. The entire family is considered important for maintaining healthy cell division across the cell cycle. Cdk12 belongs to the subclass of Cdk proteins which are particularly effective in the regulation of gene transcription. Cdk12 is further implicated in RNA splicing, translation, and the DNA damage response. Accordingly, cancers harboring a mutated Cdk12 protein, or cancers characterized by a reduced expression of a Cdk protein, may be particularly susceptible to treatment with a drug causing replication stress (e.g., a Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0190] In some embodiments, the replication stress biomarker is a CDK12 mutation. In some embodiments, the cancer to be treated by a method of the present disclosure includes a CDK12 mutation. In some embodiments, the CDK12 mutation is a loss-of-function mutation.

[0191] CDK4 and CDK6 Biomarkers

[0192] Cyclin-dependent kinase 4 (Cdk4; encoded for by the CDK4 gene) and cyclin-dependent kinase 6 (Cdk6; encoded for by the CDK6 gene) are both members of the cyclin dependent kinase (Cdk) family of cell-cycle serine-threonine kinases. Cdk4 and Cdk6 both belong to a subclass of Cdk proteins which regulate progression through the cell cycle. Cdk4 and Cdk6 are both highly implicated in regulating the cellular transition between G1 phase and S phase of the cell cycle. As such, CDK4 and CDK6 are common drug targets in cancer treatment, as inhibition of Cdk4 or Cdk6 arrests cellular development in the G1 phase, and thereby prevent or slow mitosis. Some cancers (e.g., cancers including a CDK4 mutation or a CDK6 mutation) have been found to be resistant to chemotherapeutic treatment with a Cdk4 or Cdk6 inhibitor. Accordingly, cancers which are include a CDK4 mutation or a CDK6 mutation (or are resistant to chemotherapeutic treatment with an inhibitor of Cdk4 or Cdk6) are under a high degree of replication stress and therefore may be particularly susceptible to treatment with a drug causing replication stress. In some embodiments, the CDK4 mutation is a loss-of-function mutation. In some embodiments, the CDK6 mutation is a loss-of-function mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a CDK4 mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a CDK6 mutation. In some embodiments, the cancer to be treated is resistant to treatment with a Cdk4 inhibitor a Cdk6 inhibitor, or a CDK 4 / 6 inhibitor (e.g., palbociclib, ribociclib, and abemaciclib).

[0193] CDKN2A Biomarkers p16 (alternatively known as p16INK4a) and p14arf (both encoded for by the CDKN2A gene) are naturally produced Cdk4 and Cdk6 inhibitors. A mutation to CDKN2A (particularly loss-of-function mutation) may result in non-functional or reduced-function may serve to increase the expression of Cdk4 and Cdk6, thereby serving as a replication stress mutation. Accordingly, cancers harboring a CDKN2A mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy). In some embodiments, the replication stress biomarker is a CDKN2A mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a CDKN2A mutation. In some embodiments, the CDKN2A mutation is a loss-of-function mutation.

[0194] CDC25A Biomarkers

[0195] M-phase inducer phosphatase 1 (Cdc25A; encoded by the CDC25A gene). Cdc25A is a regulatory protein phosphatase which serves to remove inhibitory phosphorylation events from Cdk proteins (in particular, Cdk2, Cdk4, and Cdk6). Accordingly, mutations to CDC25A (particularly gain-of- function mutation) may decrease phosphorylation of a Cdk protein, thereby increasing the activity of the Cdk protein and placing the cell in replicative stress. Accordingly, cancers harboring a CDC25A mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy). In some embodiments, the replication stress biomarker is a CDC25A mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a gain-of-function CDC25A mutation.

[0196] EGFR Biomarkers

[0197] The epidermal growth factor receptor (Egfr, alternatively referred to as Herl or ErbB1 ; encoded for by the EGFR gene) and is a transmembrane glycoproteins including an extracellular domain capable of binding to extracellular growth factors (e.g., epidermal growth factor (Egf), heparin binding Efg-like growth factor (Hbegf), betacellulin (Btc), amphiregulin (Areg), epiregulin (Ereg), epigen (Epgn), etc.) and an intracellular domain including a tyrosine-kinase domain. Binding of extracellular growth factor proteins to the extracellular domain promotes a confirmational change in the intracellular tyrosine-kinase domain, which in turn activates intracellular signaling pathways, particularly those associated with cell division (e.g., the Ras / Mapk pathway). Through this mechanism, Egfr serves to transduce extracellular signals (e.g., those from extracellular polypeptide growth factor), into intracellular signals (e.g., as a part of the Ras / Mapk pathway) to promote cell division. Mutations to EGFR may result in a confirmational change to the tyrosine-kinase domain, independent of any interaction with an extracellular growth factor peptide, causing a perpetual activation of cell signals to undergo cell division. Egfr mutations are commonly observed in many cancers and are particularly common in lung cancer. Accordingly, cancers harboring a EGFR mutation (e.g., a gain-of-function mutation) may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0198] In some embodiments, the replication stress biomarker is an EGFR mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes an EGFR mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a gain-of-function EGFR mutation. FBXW7 Biomarkers

[0199] Proteins containing at least one F-box domain (referred to as F-box proteins; e.g., the Fbxw7 protein encoded for by the gene FBXW7), in particular FBXW7, is frequently mutated in several cancer types including endometrial, colorectal, and gastric, ranging in frequency from 5-35%. FBXW7 driver mutations are observed in the more aggressive subtypes of endometrial cancer including UCS (~35%) and USC (~25%). FBXW7 has a diverse spectrum of loss-of-function mutations in cancer including truncating mutations peppered across the gene and missense mutations within the Cyclin E1 recognizing WD40 repeats. Fbxw7 functions as a homodimer within the SCF complex and many deleterious missense mutations within the WD40 repeats are mostly heterozygous and dominant negative. Remarkably, several recurring hotspot missense mutations are found in the WD40 repeats including R465, R479, and R505 - all of which disrupt Cyclin E1 binding and ubiquitylation. Accordingly, cancers harboring a FBXW7 mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0200] In some embodiments, the cancer may include a FBXW7 mutation (e.g., a loss of function mutation). In some embodiments, the cancer includes at least one other replication stress biomarker (e.g., a replication stress biomarker described herein) and a FBXW7 mutation. c-MYC Biomarkers

[0201] The Myc family of cell signaling proteins includes c-Myc, l-Myc, and n-Myc. c-Myc, l-Myc, and n- Myc are encoded for by the c-MYC, l-MYC, and n-MYC genes respectively. The MYC genes perform several regulatory processes across cellular functions, many of which are associated with cell division, cell proliferation, and DNA replication. Myc proteins aid in the regulation of almost 15% of all genes. Mutations in MYC genes, in particular mutations in c-MYC, are commonly found in cancer, wherein the mutation results in, e.g., uncontrolled cell division. Many c-MYC associated cancers are commonly considered undruggable, precluding conventional chemotherapeutic approaches. However, cancers harboring a mutation to a gene encoding a Myc protein (e.g., a mutation to c-MYC) mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., a Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0202] In some embodiments, the replication stress biomarker is a c-MYC mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a gain-of- function c-MYC mutation. In some embodiments, the cancer to be treated includes gene amplification of a c-MYC gene.

[0203] PIK3CA Biomarkers

[0204] Phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (Pik3ca, alternatively referred to as P110a; encoded for by the PIK3CA gene) is the catalytic subunit of phosphatidylinositol- 4,5-bisphosphate 3-kinase (Pi3k). Pik3ca uses ATP to phosphorylate phosphatidylinositols (Ptdlns) such as Ptdlns4P, Ptdlns(3,4)P2, Ptdlns(3,4,5)P3, and Ptdlns(4,5)P2. Ptdlns may then bind to protein kinase B (PKB or alternatively AKT) Through this phosphorylation pathway, PI3K plays an important role in cell signaling, such as the Pi3k / Akt / mtor pathway. The Pi3k / Akt / mtor pathway is a critical inducer tissue growth in cells. As a result, mutations to Pi3k, in particular gain-of-function mutations to the Pik3ca subunit, are implicated in many cancers. For example, nearly one-third of breast and cervical cancers include a PIK3CA mutation. Further, PIKC3A mutations may result in a number of genetic disorders resulting in the overgrowth of body parts in a subject, collectively referred to as Pik3ca-overgrowth spectrum (PROS). Accordingly, cancers harboring a mutation in a Pi3k gene (e.g., a mutation to the Pik3ca subunit) may be particularly susceptible to treatment with a drug causing replication stress (e.g., a Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0205] In some embodiments, the replication stress biomarker is a mutation in a PI3K protein. In some embodiments, the replication stress biomarker is a PIK3CA mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a gain-of-function PIK3CA mutation.

[0206] PPP2R1A Biomarkers

[0207] Serine / threonine-protein phosphatase 2A 65kDa regulatory subunit A alpha isoform (Ppp2r1a, encoded by the PPP2R1A gene) is a regulatory subunit of protein phosphatase 2 (Pp2a), one of the four major Ser / Thr phosphatases. Pp2a is broadly responsible for phosphorylating several cell division signaling pathways. Pp2a is implicated for its role in regulating tumor production by controlling phosphorylation events in cell signaling pathways. Mutation to PPP2R1A (e.g., loss-of-function mutations), result in the loss of Pp2a’s ability to regulate phosphorylation events, removing a critical biological response to cancer-causing mutations. PPP2R1A mutations are commonly observed in endometrial cancer, ovarian cancer, and uterine cancer. Accordingly, cancers harboring a PPP2R1A mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0208] In some embodiments, the replication stress biomarker is a PPP2R1A mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes PPP2R1A mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a loss-of-function PPP2R1A mutation.

[0209] PTEN Biomarkers

[0210] Phosphatase and tensin homolog (Pten; encoded for by the PTEN gene) is a cell-cycle regulating phosphatase. Unlike many other protein tyrosine phosphatases, Pten preferentially dephosphorylates phosphoinositide substrates. Pten plays a role in the regulation of several cell signaling pathways, including the Akt / Pkb signaling pathway. PTEN is commonly observed to be mutated (e.g., a loss-of- function mutation) in tumor cells. PTEN mutations are commonly observed in breast cancer, prostate cancer, bladder cancer, lung cancer, endometrial cancer, lung cancer, melanoma, and head and neck cancer. Accordingly, cancers harboring a PTEN mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., a Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0211] In some embodiments, the replication stress biomarker is a PTEN mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a PTEN mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a loss-of-function PTEN mutation. RB1 Biomarkers

[0212] The retinoblastoma protein (RB, or alternatively pRB; encoded for by the RB1 gene) is a cell cycle protein which serves to suppress cell cycle progression in cells by binding to transcription factor proteins (e.g., E2 promoter binding protein dimerization partner (E2F-DP) dimers), preventing the transduction of signals therefrom. Once the cell has sufficiently grown and / or received a signal to begin cell division, pRB is phosphorylated by CDK proteins, thereby inactivating pRB, allowing cell division to progress. Cancers associated with RB1 mutations include brain cancer, bone cancer, muscle cancer, prostate cancer, uterine cancer, breast cancer, lung cancer, and melanoma. Mutations to RB1 (e.g., loss of function mutations) may result in permanently inactive pRB, thereby causing uncontrolled cell division. Accordingly, cancers harboring a RB1 mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0213] In some embodiments, the replication stress biomarker is a RB1 mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a loss-of-function RB1 mutation.

[0214] BRAF Biomarkers

[0215] The Braf protein BRAF (encoded for by the BRAF gene) is a member of the Raf family of proteins. The Raf family of proteins also includes Araf (encoded for by the ARAF gene) and Craf (encoded for by the CRAF gene), which play a critical role in several cell signaling pathways, including the Ras / Mapk pathway. Raf proteins are the second step in the Ras / Mapk pathway, and therefore wild type Raf proteins require interaction with a Ras protein to transduce a cellular signal. Similar to mutated Ras proteins (e.g., as described above), mutations to Raf proteins commonly prevent dephosphorylation of the phosphorylated Raf complex, resulting in a continuous cellular signal to undergo cell division processes, which may result in the development of tumors. Cancers associated with a BRAF mutations include melanoma, leukemia, lymphoma, and lung cancer. Cancer harboring a BRAF mutation may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0216] In some embodiments, the replication stress biomarker is a BRAF mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a BRAF mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a gain-of-function BRAF mutation.

[0217] HPV Biomarkers

[0218] The human papillomavirus (HPV) is a DNA virus commonly associated with the development of cancers in subjects previously suffering therefrom. HPV is commonly observed to cause DNA damage (e.g., mutations, e.g., replication stress mutations) to subjects. Even after the subject is cured of HPV (e.g., by removal of viral particles from the subject or relief of a symptom associated therewith), the DNA damage may result in tumor growth or the development of a cancer in the subject. HPV infections are known to result in cervical cancer, penile cancer, vaginal cancer, vulvar cancer, colorectal cancer, and throat cancer. In particular, some reports demonstrate that more than 90% of cervical cancers are associated with a prior or current HPV infection. Accordingly, cancers associated with or resulting from infection with HPV may be particularly susceptible to treatment with a drug causing replication stress (e.g., an Myt1 inhibitor, e.g., any one of compounds 1 to 328, optionally administered as a combination therapy).

[0219] In some embodiments, the replication stress biomarker is an HPV infection. In some embodiments, the cancer treated by a method of the present disclosure developed in a patient previously infected with HPV. In some embodiments, the prior infection with HPV resulted in DNA damage. In some embodiments, the DNA damage causes a replication stress mutation. In some embodiments, the replication stress mutation is a CDKN2A mutation. In some embodiments, the cancer to be treated by the methods of the present disclosure includes a loss-of-function CDKN2A mutation.

[0220] Myt1 Inhibitors

[0221] The compound used in the methods of the invention may be, e.g., a compound of formula (I):

[0222] (i); or a pharmaceutically acceptable salt thereof, wherein: each of X, Y, and Z is independently N or CR2;

[0223] R1and each R2are independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Cs-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, cyano, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B; or R1combines with one R2that is vicinal to R1to form an optionally substituted C3-6 alkylene; each of R3and R4is independently optionally substituted C1-6 alkyl or halogen;

[0224] R5is H or -N(R7)2;

[0225] R6is -C(O)NH(R8), -C(O)R7A, or -S02R7A; each R7is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted Cs-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or -SC>2R7A; or two R7groups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R7Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted Cs-w aryl; each R7Bis independently hydroxyl, optionally substituted C1-6 alkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -N(R7)2, -C(O)N(R8)2, - SO2N(R8)2, -SC>2R7A, or optionally substituted alkoxy; each R8is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkoxyalkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C3-8cycloalkyl, or optionally substituted C1-9heteroaryl; or two R8, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; and Q is optionally substituted C1-6alkylene, optionally substituted C2-6alkenylene, optionally substituted C2-6alkynylene, optionally substituted C3-8cycloalkylene, optionally substituted C3-8cycloalkenylene optionally substituted C6-10arylene, optionally substituted C2-9heterocyclylene, or optionally substituted C1-9 heteroarylene; wherein the C2-9heterocyclyl, C2-9heterocyclyl C1-6alkyl, C1-9heteroaryl, and C1-9heteroaryl C1-6alkyl groups each contain one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Preferably, the compound of formula (I) is enriched for the atropisomer of formula (IA): (IA); where all variables are as described herein. The compound used in the methods of the invention may be, e.g., a compound of formula (II): (II); where all variables are as described herein. Preferably, the compound of formula (II) is enriched for the atropisomer of formula (IIA): (IIA); where all variables are as described herein. The compound used in the methods of the invention may be, e.g., a compound of formula (III): where R2Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C2-9heterocyclyl, optionally substituted C2-9heterocyclyl C1-6alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, –N(R7)2, –OR7, –C(O)N(R8)2, –SO2N(R8)2, –SO2R7A, or –Q–R7B. Preferably, the compound of formula (III) is enriched for the atropisomer of formula (IIIA): The compound used in the methods of the invention may be, e.g., a compound listed in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1

[0226] The methods of the invention include (where possible) individual diastereomers, enantiomers, epimers, and atropisomers of the compounds disclosed herein, and mixtures of diastereomers and / or enantiomers thereof including racemic mixtures. Although the specific stereochemistries disclosed herein are preferred, other stereoisomers, including diastereomers, enantiomers, epimers, atropisomers, and mixtures of these may also have utility in treating Myt1 -mediated diseases. Inactive or less active diastereoisomers and enantiomers may be useful, e.g., for scientific studies relating to the receptor and the mechanism of activation.

[0227] It is understood that certain molecules can exist in multiple tautomeric forms. This invention includes all tautomers even though only one tautomer may be indicated in the examples.

[0228] The invention also includes pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions that contain the compounds and a pharmaceutically acceptable carrier. The compounds are especially useful, e.g., in certain kinds of cancer and for slowing the progression of cancer once it has developed in a patient.

[0229] The compounds disclosed herein may be used in pharmaceutical compositions including (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier. The compounds may be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients. The compounds may also be used in pharmaceutical compositions in which the compound disclosed herein or a pharmaceutically acceptable salt thereof is the only active ingredient.

[0230] Optical Isomers - Diastereomers - Geometric Isomers - Tautomers

[0231] Compounds disclosed herein may contain, e.g., one or more stereogenic centers and can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers and / or enantiomers. The invention includes all such isomeric forms of the compounds disclosed herein. It is intended that all possible stereoisomers (e.g., enantiomers and / or diastereomers) in mixtures and as pure or partially purified compounds are included within the scope of this invention (i.e., all possible combinations of the stereogenic centers as pure compounds or in mixtures).

[0232] Some of the compounds described herein may contain bonds with hindered rotation such that two separate rotomers, or atropisomers, may be separated and found to have different biological activity which may be advantageous. It is intended that all of the possible atropisomers are included within the scope of this invention.

[0233] Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. An example is a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed by the invention.

[0234] Compounds disclosed herein having one or more asymmetric centers may be separated into diastereoisomers, enantiomers, and the like by methods well known in the art.

[0235] Alternatively, enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and / or reagents of known configuration.

[0236] Metabolites - Prodrugs

[0237] The invention includes therapeutically active metabolites, where the metabolites themselves fall within the scope of the claims. The invention also includes prodrugs, which are compounds that are converted to the claimed compounds as they are being administered to a patient or after they have been administered to a patient. The claimed chemical structures of this application in some cases may themselves be prodrugs.

[0238] Isotopically Enriched Derivatives

[0239] The invention includes molecules which have been isotopically enriched at one or more position within the molecule. Thus, compounds enriched for deuterium fall within the scope of the claims.

[0240] Methods of Preparing Myt1 inhibitors

[0241] Methods of preparing Myt1 inhibitors are known in the art (see, e.g., International Patent Publication No. WO 2022 / 213204, the entirety of which is incorporated herein by reference).

[0242] Combination Therapies

[0243] In some embodiments, the Myt1 inhibitor is administered as a combination therapy, i.e., in combination with a second active pharmaceutical ingredient. In some embodiments, the second active pharmaceutical ingredient is selected from a Wee1 inhibitor, a Fen1 inhibitor, a Topi inhibitor, an Rrm1 inhibitor, an Rrm2 inhibitor, an Aurkb inhibitor, a Top2A inhibitor, an Atr inhibitor, a Ttk inhibitor, an Sod1 inhibitor, an Sod2 inhibitor, a Bub1 inhibitor, a Cdc7 inhibitor, a Sae1 inhibitor, a Plk1 inhibitor, Uba2 inhibitor, a Dut inhibitor, an Hdac3 inhibitor, a Chekl inhibitor, an Aurka inhibitor, a Men1 inhibitor, a Doti I inhibitor, a Crebbp inhibitor, an Ezh2 inhibitor, a Plk4 inhibitor, an Haspin inhibitor, a Mettl3 inhibitor, a nucleoside analog, a platinum-based DNA damaging agent, or a combination thereof.

[0244] Atr Inhibitors

[0245] Atr inhibitors 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 pM or less (e.g., 5 pM or less or 1 pM or less). For certain Atr 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 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Examples of Atr inhibitors are: elimusertib (BAY1895344) ceralasertib (AZD6738) berzosertib (VE-822)

[0246] SKLB-197 or a pharmaceutically acceptable salt thereof.

[0247] In one embodiment, an Atr inhibitor is a compound of formula (IV): or a pharmaceutically acceptable salt thereof, where is a double bond, and each W is independently N or CR12; or is a single bond, and each W is independently NRW, carbonyl, or C(RW)2; where each RWis independently H or optionally substituted C1-6 alkyl; R9is optionally substituted C1-6alkyl or H; R10is optionally substituted C2-9heterocyclyl, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-9heterocyclyl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, – N(R13)2, –OR13, –CON(R14)2, –SO2N(R14)2, –SO2R13A, or –U–R13B; R11is optionally substituted C1-9heteroaryl or optionally substituted C1-9heteroaryl C1-6alkyl; each R12is independently hydrogen, halogen, optionally substituted C1-6alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R13is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9heteroaryl, or –SO2R13A; or both R13, together with the atom to which they are attached, combine to form an optionally substituted C2-9heterocyclyl; each R13Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10aryl; R13Bis hydroxyl, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9 heteroaryl, –N(R13)2, –CON(R14)2, –SO2N(R14)2, –SO2R13A, or optionally substituted alkoxy; each R14is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkoxyalkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R14, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; U is optionally substituted C2-9heterocyclylene, optionally substituted C3-8cycloalkylene, optionally substituted C1-9heteroarylene, or optionally substituted C6-10arylene; and V is hydrogen or halogen. The Atr inhibitor may be, e.g., a compound of formula (V): or a pharmaceutically acceptable salt thereof, where each W is independently N or CR4; R9is optionally substituted C1-6alkyl or H; R10is optionally substituted C2-9heterocyclyl, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-9heterocyclyl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, – N(R13)2, –OR13, –CON(R14)2, –SO2N(R14)2, –SO2R13A, or –U–R13B; R11is optionally substituted C1-9heteroaryl or optionally substituted C1-9heteroaryl C1-6alkyl; each R12is independently hydrogen, halogen, optionally substituted C1-6alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R13is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9heteroaryl, or –SO2R13A; or both R13, together with the atom to which they are attached, combine to form an optionally substituted C2-9heterocyclyl; each R13Ais independently optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, or optionally substituted C6-10aryl; R13Ais hydroxyl, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9 heteroaryl, –N(R13)2, –CON(R14)2, –SO2N(R14)2, –SO2R13A, or optionally substituted alkoxy; each R14is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkoxyalkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R14, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; U is optionally substituted C2-9heterocyclylene, optionally substituted C3-8cycloalkylene, optionally substituted C1-9heteroarylene, or optionally substituted C6-10arylene; and V is hydrogen or halogen. In some embodiments, in the compound of formula (IV) or (V): each W is independently N or CR12; R9is H or optionally substituted C1-6alkyl; R10is optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, –N(R13)2, –CON(R14)2, –SO2N(R14)2, or –SO2R13A; R11is optionally substituted C1-9heteroaryl; each R12is independently H or optionally substituted C1-6 alkyl; each R13is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9heteroaryl, or –SO2R13A, where each R13Ais independently optionally substituted C1-6alkyl or optionally substituted C3-8cycloalkyl; or both R13, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R13Ais independently optionally substituted C1-6alkyl or optionally substituted C3-8cycloalkyl; and each R14is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl.

[0248] Methods of making compounds of formula (IV) are described, e.g., in International Application No. PCT / US2019 / 051539, hereby incorporated by reference. The Atr inhibitor may be, e.g., a compound of formula (IV-a): or a pharmaceutically acceptable salt thereof, where W, R9, R10, R11, and R12are as described for formula (III). The Atr inhibitor may be, e.g., a compound of formula (IV-b): or a pharmaceutically acceptable salt thereof, where W, R9, R10, R11, and R12are as described for formula (IV). The Atr inhibitor may be, e.g., a compound of formula (IVA): or a pharmaceutically acceptable salt thereof, where R9, R10, R11, and R12are as described for formula (IV).

[0249] The Atr inhibitor may be, e.g., a compound of formula (IVA-a):

[0250] (IVA-a), or a pharmaceutically acceptable salt thereof, where R9, R10, R11, and R12are as described for formula (IV).

[0251] The Atr inhibitor may be, e.g., a compound of Formula (IVB): or a pharmaceutically acceptable salt thereof, where R9, R10, R11, and R12are as described for formula (IV).

[0252] The Atr inhibitor may be, e.g., a compound of formula (IVB-a): or a pharmaceutically acceptable salt thereof, where R9, R10, R11, and R12are as described for formula (IV).

[0253] The Atr inhibitor may be, e.g., a compound of Formula (I IIC):

[0254] or a pharmaceutically acceptable salt thereof, where R9, R10, R11, and R12are as described for formula (IV). The Atr inhibitor may be, e.g., a compound of formula (IHC-a): or a pharmaceutically acceptable salt thereof, where R9, R10, R11, and R12are as described for formula (IV). The Atr inhibitor may be, e.g., a compound of formula (IVD): or a pharmaceutically acceptable salt thereof, where R9, R10, R11, and R12are as described for formula (IV). The Atr inhibitor may be, e.g., a compound of formula (IVD-a): or a pharmaceutically acceptable salt thereof, where R9, R10, R11, and R12are as described for formula (IV).

[0255] Preferably, R9is methyl.

[0256] In some embodiments, R10may be, e.g., optionally substituted C3-8 cycloalkyl. For example, R10may be a group of formula (A):

[0257] (A) where n is 0, 1 , 2, or 3; and

[0258] R10Ais hydrogen, alkylsulfonyl, cyano, -CON(RA)2, -SON(RA)2, optionally substituted C1-9 heteroaryl, hydroxy, or alkoxy, where each RAis independently H or alkyl; or both RA, together with the atom to which they are attached, combine to form C2-9 heterocyclyl.

[0259] In some embodiments, R10may be, e.g., optionally substituted C1-6 alkyl (e.g., optionally substituted tertiary Cz-e alkyl. For example, R10may be a group of formula (B): hydrogen, alkylsulfonyl, cyano, -CON(RA)2, -SON(RA)2, optionally substituted C1-9 heteroaryl, hydroxy, or alkoxy, where each RAis independently H or alkyl; or both RA, together with the atom to which they are attached, combine to form C2-9 heterocyclyl.

[0260] In some embodiments, R10may be, e.g., optionally substituted non-aromatic C2-9 heterocyclyl.

[0261] In some embodiments, R10may be, e.g.:

[0262]

[0263] In some embodiments, R11may be, e.g., optionally substituted, monocyclic C1-9 heteroaryl including at least one nitrogen atom (e.g., two nitrogen atoms). For example, R11may be a group of formula where A-ring is optionally substituted, monocyclic C1-9 heteroaryl ring.

[0264] In some embodiments, A-ring may be, e.g., a group of formula (C1): where R19is hydrogen, halogen, or optionally substituted C1-6 alkyl.

[0265] In some embodiments, R11may be, e.g.:

[0266] In some embodiments, R11may be, e.g.:

[0267] In some embodiments, R12may be, e.g., hydrogen.

[0268] The Atr inhibitor may be, e.g., a compound listed in Table 2 or a pharmaceutically acceptable salt thereof.

[0269] Table 2

[0270]

[0271] Compound A121 may be referred to interchangeably using the name “camonsertib” herein.

[0272] An Atr inhibitor may be isotopically enriched (e.g., enriched for deuterium).

[0273] Further non-limiting examples of Atr inhibitors include, e.g., those described in, e.g., International Application Publication Nos. WO 2020087170, WO 2018218197, WO 2020259601 , WO 2019036641 , WO 2020049017, WO 2019154365, WO 2020103897, WO 2021233376, WO 2022028598, WO 2022012484, WO 2022002245, and WO 2022002243, each of which is incorporated by reference herein; U.S. Patent Nos. 11 ,028,076, 10,745,420, 10,301 ,324, 10,196,405, 9,663,535, 9,549,932, 8,552,004, and 8,841 ,308, each of which is incorporated by reference herein; and U.S. Patent Application Publication Nos. 2019 / 0055240 and 2019 / 0300547, each of which is incorporated by reference herein.

[0274] An Atr inhibitor may be isotopically enriched (e.g., enriched for deuterium).

[0275] Aurka Inhibitors

[0276] Aurka inhibitors may be compounds that upon contacting Aurka, whether in vitro, in cell culture, or in an animal, reduce the activity of Aurka, such that the measured Aurka IC50 is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain Aurka inhibitors, Aurka 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, Aurka IC50 is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Examples of Aurka inhibitors are: MK- 0457 (tozasertib; CAS No.: CAS No.: 639089-54-6), barasertib (AZD1152) (CAS No.: 722543-31-9), PHA739358 (CAS No.: 827318-97-8), AT9283 (CAS No.: 896466-0409), AMG900 (CAS No.: 945595-80- 2), SNS-314 (CAS No.: 1146618-41-8), TAK-901 (CAS No.: 934541-31-8), CYC116 (CAS No.: 693228- 63-6), GSK1070916 (CAS No.: 942918-07-2), PF03814735 (CAS No.: 942487-16-3), and pharmaceutically acceptable salts thereof. Exemplary Aurka inhibitors are also disclosed in US 6,977,259; US 6,919,338; US 7,105,669; US 7,214,518; US 7,235,559; US 7,402,585; US 7,709,479; US 8,026,246; US 8,138,338; US 8,377,983; US 9,567,329; US 9,637,474; US 20060178382; US 20090029992; and US 20190352297; the Aurka inhibitors disclosed therein are incorporated herein by reference in their entirety.

[0277] Aurkb Inhibitors

[0278] Aurkb inhibitors may be compounds that upon contacting Aurkb, whether in vitro, in cell culture, or in an animal, reduce the activity of Aurkb, such that the measured Aurkb IC50 is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain Aurkb inhibitors, Aurkb 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, Aurkb IC50 is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Examples of Aurkb inhibitors are: MLN8237 (CAS No.: 1028486-01-2), MK-0457, MLN8054 (CAS No.: 869363-13-3), PHA739358 (CAS No.: CAS No. 827318-97-8), AT9283 (CAS No.: 896466-04-9), AMG900 (CAS No. : 945595-80-2), MK5108 (CAS No.: 1010085-13-8), SNS314 (CAS No.: 1146618-41-8), TAK901 (CAS No.: 934541-31-8), CYC116 (CAS No.: 693228-63-6), ENMD2076 (CAS No.: 934353-76-1), and pharmaceutically acceptable salts thereof. Exemplary Aurkb inhibitors are also disclosed in US 7,560,551 ; US 7,977,477; US 8,110,573; and US 20110293745; the Aurkb inhibitors disclosed therein are incorporated herein by reference in their entirety.

[0279] Bub1 Inhibitors

[0280] Bub1 inhibitors may be compounds that upon contacting Bub1 , whether in vitro, in cell culture, or in an animal, reduce the activity of Bub1 , such that the measured Bub1 IC50 is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain Bub1 inhibitors, Bub1 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, Bub1 IC50 is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Examples of Bub1 inhibitors are: BAY- 320 (CAS No.: 1445830-50-1), BAY-419, BAY1816032 (CAS No. : 1891087-61-8), and pharmaceutically acceptable salts thereof. Exemplary Bub1 inhibitors are also disclosed in US 9,265,763; US 9,416,125; US 9,745,285; US 10,266,548; US 10,428,044; US 20150141372; US 20160145267; US 20160046604; US 20160046610; US 20170275269; US 20170305882; the Bub1 inhibitors disclosed therein are incorporated herein by reference in their entirety.

[0281] Cdc7 Inhibitors

[0282] Cdc7 inhibitors may be compounds that upon contacting Cdc7, whether in vitro, in cell culture, or in an animal, reduce the activity of Cdc7, such that the measured Cdc7 IC50 is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain Cdc7 inhibitors, Cdc7 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, Cdc7 IC50 is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Examples of Cdc7 inhibitors are: SRA141 , TAK931 (CAS No.: 1330782-76-7), and pharmaceutically acceptable salts thereof. Exemplary Cdc7 inhibitors are also disclosed in US 7,279,575; US 8,314,121 ; US 8,383,624; US 8,658,662; US 8,691 ,828; US 9,156,824; US 9,180,105; US 9,974,795; US 10,745,510; US 20050043346; US 20050256121 ; US 20070293491 ; US 20190336502; and US 20200093828; the Cdc7 inhibitors disclosed therein are incorporated herein by reference in their entirety.

[0283] Chekl Inhibitors

[0284] Chekl inhibitors may be compounds that upon contacting Chekl , whether in vitro, in cell culture, or in an animal, reduce the activity of Chekl , such that the measured Chekl IC50 is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain Chekl inhibitors, Chekl 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, Chekl IC50 is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Examples of Chekl inhibitors are: SRA737 (CAS No.: 1489389-18-5), and pharmaceutically acceptable salts thereof. Exemplary Chekl inhibitors are also disclosed in US 7,067,506; US 8,093,244; US 8,410,279; US 8,530,468; US 8,618,121 ; 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 Chekl inhibitors disclosed therein are incorporated herein by reference in their entirety.

[0285] Crebbp Inhibitors

[0286] Crebbp inhibitors may be compounds that upon contacting Crebbp, whether in vitro, in cell culture, or in an animal, reduce the activity of Crebbp, such that the measured Crebbp IC50 is 10 pM or less (e.g., 5 pM or less or 1 pM or less). For certain Crebbp inhibitors, Crebbp 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, Crebbp IC50 is 0.1 nM to 1 pM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Examples of Crebbp inhibitors are: CPI4, CCS1477 (CAS No.: 2222941-37-7), E7386 (CAS No.: 1799824-08-0), NEO1132, NEO2734 (CAS No.: 2081072-29-7), PRI724 (CAS No.: 1422253-38-0), C82 (CAS No.: 691862-35-8), BC001 , C646 (CAS No.: 328968-36-1), EML425 (CAS No.: 1675821-32-5), CBP30 (CAS No.: 1613695- 14-9), and pharmaceutically acceptable salts thereof. Exemplary Crebbp inhibitors are also disclosed in US 9,763,922; US 10,206,931 ; US 10,696,655; US 10,870,648; US 20190270797; US 20190298729; and US 20190308978; the Crebbp inhibitors disclosed therein are incorporated herein by reference in their entirety. Dot1l Inhibitors Dot1l inhibitors may be compounds that upon contacting Dot1l, whether in vitro, in cell culture, or in an animal, reduce the activity of Dot1l, such that the measured Dot1l IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Dot1l inhibitors, Dot1l 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, Dot1l 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). Examples of Dot1l inhibitors are: pinometostat (EPZ5676) (CAS No.: 1380288-87-8) and pharmaceutically acceptable salts thereof. Exemplary Dot1l inhibitors are also disclosed in US 8,722,877; US 9,458,165; US 10,112,968; US 20140100184; US 20150342979; and US 20170335402; the Dot1l inhibitors disclosed therein are incorporated herein by reference in their entirety. Dut Inhibitors Dut inhibitors may be compounds that upon contacting Dut, whether in vitro, in cell culture, or in an animal, reduce the activity of Dut, such that the measured Dut IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Dut inhibitors, Dut IC50may 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, Dut 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). Examples of Dut inhibitors are: TAS114 (CAS No.: 1198221-21-4) and pharmaceutically acceptable salts thereof. Exemplary Dut inhibitors are also disclosed in US 7,601,702; US 8,530,490; US 9,790,214; US 9,809,571; US 10,544,105; US 10,562,860; US 10,570,100; US 10,577,321; US 10,829,457; US 10,858,344; US 20110212467; US 20190270756; US 20190330158; US 20190330210; and US 20200039966; the Dut inhibitors disclosed therein are incorporated herein by reference in their entirety. Ezh2 Inhibitors Ezh2 inhibitors may be compounds that upon contacting Ezh2, whether in vitro, in cell culture, or in an animal, reduce the activity of Ezh2, such that the measured Ezh2 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Ezh2 inhibitors, Ezh2 IC50may 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, Ezh2 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). Examples of Ezh2 inhibitors are: EPZ-6438 (CAS No.: 1403254-99-8), GSK126 (CAS No.: 1346574-57-9), and pharmaceutically acceptable salts thereof. Exemplary Ezh2 inhibitors are also disclosed in US 8,691,507; US 9,394,283; US 9,889,138; US 10,166,238; US 10,040,782; US 10,457,640; US 10,633,371; US 10,647,700; US 10,786,511; US 20190328743; US 20190345139; and US 20210052595; the Ezh2 inhibitors disclosed therein are incorporated herein by reference in their entirety. Haspin Inhibitors Haspin inhibitors may be compounds that upon contacting Haspin, whether in vitro, in cell culture, or in an animal, reduce the activity of Haspin, such that the measured Haspin IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Haspin inhibitors, Haspin IC50may 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, Haspin 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). Examples of Haspin inhibitors are: SEL120 (CAS No.: 1609452-30-3) and pharmaceutically acceptable salts thereof. Exemplary Haspin inhibitors are also disclosed in US 20130102627 and US 20130231360; the Haspin inhibitors disclosed therein are incorporated herein by reference in their entirety. Hdac3 Inhibitors Hdac3 inhibitors may be compounds that upon contacting Hdac3, whether in vitro, in cell culture, or in an animal, reduce the activity of Hdac3, such that the measured Hdac3 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Hdac3 inhibitors, Hdac3 IC50may 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, Hdac3 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). Examples of Hdac3 inhibitors are: RGFP966 (CAS No.: 1396841-57-8) and pharmaceutically acceptable salts thereof. Exemplary Hdac3 inhibitors are also disclosed in US 8,716,344; US 9,096,549; US 10,029,988; US 10,059,723; and US 20190216754; the Hdac3 inhibitors disclosed therein are incorporated herein by reference in their entirety. Fen1 Inhibitors Fen1 inhibitors may be compounds that upon contacting Fen1, whether in vitro, in cell culture, or in an animal, reduce the activity of Fen1, such that the measured Fen1 IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Fen1 inhibitors, Fen1 IC50may 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, Fen1 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). Examples of Fen1 inhibitors are: C8 (PMID: 32719125), SC13 (CAS No.: 2098776-03-3), Fen1-IN-3 (CAS No.: 2109805-87-8), and pharmaceutically acceptable salts thereof. Exemplary Fen1 inhibitors are also disclosed in US 20200237763 and US 7,927,790; the Fen1 inhibitors disclosed therein are incorporated herein by reference in their entirety. Men1 Inhibitors Men1 inhibitors may be compounds that upon contacting Men1, whether in vitro, in cell culture, or in an animal, reduce the activity of Men1, such that the measured Men1 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Men1 inhibitors, Men1 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, Men1 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). Examples of Men1 inhibitors are: MI3454 (CAS No.: 2134169-43-8), SNDX5613 (CAS No.: 2169919-21-3), VTP50469 (CAS No.: 2169916- 18-9), KO539 (zifomenib; CAS No.: 2134675-36-6), and pharmaceutically acceptable salts thereof. Exemplary Men1 inhibitors are also disclosed in US 8,242,078’ US 9,212,180; US 10,077,271; US 10,526,341; US 10,611,778; US 10,745,409; US 10,752,639; US 10,781,218; US 10,899,738; US 20170119769; US 20190010167; US 20190211036; US 20200022953; US 20200216471; and US 20200223853; the Men1 inhibitors disclosed therein are incorporated herein by reference in their entirety. Mettl3 Inhibitors Mettl3 inhibitors may be compounds that upon contacting Mettl3, whether in vitro, in cell culture, or in an animal, reduce the activity of Mettl3, such that the measured Mettl3 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Mettl3 inhibitors, Mettl3 IC50may 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, Mettl3 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). Examples of Mettl3 inhibitors are: UZH1a (CAS No.: 2813577-78-3), sTC-15 (CAS No.: 2648257-56-9), and pharmaceutically acceptable salts thereof. Exemplary Mettl3 inhibitors are also disclosed in US 20160264934 and WO 2020201773; the Mettl3 inhibitors disclosed therein are incorporated herein by reference in their entirety. Nucleoside Analogs Nucleoside analogs may be compounds that can act as antimetabolites by interfering with nucleotide production, or by acting as chain terminators in DNA lengthening by polymerase enzymes, either in cell culture, or in an animal. For certain nucleoside analogs, biological activity make occur at 10 µM or less (e.g., 5 µM or less or 1 µM or less) and could be as low as 100 pM or 10 pM. Preferably, nucleoside analog activity will occur at 1 nM to 1 µM (e.g., 1 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM). Examples of nucleoside analogs are cytarabine, gemcitabine, mercaptopurine, azacytidine, cladribine, decitabine, fluorouracil, floxuridine, fludarabine or nelarabine. Plk1 Inhibitors Plk1 inhibitors may be compounds that upon contacting Plk1, whether in vitro, in cell culture, or in an animal, reduce the activity of Plk1, such that the measured Plk1 IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Plk1 inhibitors, Plk1 IC50may 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, Plk1 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). Examples of Plk1 inhibitors are: BI2536 (CAS No.: 755038-02-9), BI6727 (CAS No.: 755038-65-4), TAK960 (CAS No.: 1137868-52-0), NMSP937 (onvansertib; CAS No.: 1034616-18-6), GSK461364 (CAS No.: 929095-18-1), and pharmaceutically acceptable salts thereof. Exemplary Plk1 inhibitors are also disclosed in US 7,504,513; US 7,517,873; US 7,851,495; US 7,977,336; US 8,101,628; US 8,129,387; US 8,278,299; US 9,175,038; US 9,175,357; US 20070185133; US 20080015192; US 20100278833; US 20150368209; US 20170283445; and US 20200247796; the Plk1 inhibitors disclosed therein are incorporated herein by reference in their entirety. Plk4 Inhibitors Plk4 inhibitors may be compounds that upon contacting Plk4, whether in vitro, in cell culture, or in an animal, reduce the activity of Plk4, such that the measured Plk4 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Plk4 inhibitors, Plk4 IC50may 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, Plk4 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). Exemplary Plk4 inhibitors include compounds of formula (VI): or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; L is optionally substituted C2-9heterocyclyl, optionally substituted C2-9heteroaryl, optionally substituted C6-10 aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of RL; R15Ais hydrogen, halogen, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8 cycloalkyl, or nitrile; R15Bis hydrogen; or R15Aand R15B, together with the atoms to which they are attached, are C2-9heterocyclyl, C6-10aryl, or C1-9heteroaryl; A is O or S, and RA’and RA”are both absent; or A is N, RA’is absent, and RA”is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, or optionally substituted C1-6 alkylsulfonyl, or RA”and L, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl or optionally substituted C2-9 heteroaryl; or A is C, and each of RA’and RA”are independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; each RLis independently halogen, cyano, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, -S(O)mRLA, -N(RLB)2, or -ORLB; RLAis optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -ORLBor -N(RLB)2. each RLBis independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted 93 C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, or optionally substituted C1-6alkylsulfonyl; or two RLBgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9heterocyclyl; J is N, and R16is absent; or J is C, and R16is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, or optionally substituted C1-9 heteroaryl; R17is optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9 heteroaryl, -CONH2, or -E-R17A; E is optionally substituted amino, optionally substituted C2-9heterocyclylene, optionally substituted C2-9heteroarylene, optionally substituted C6-10arylene, or optionally substituted C3-8cycloalkylene; R17Ais hydrogen, halogen, cyano, optionally substituted C1-6 alkylsulfonyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, or optionally substituted C1-9heteroaryl; R18is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or -OR18A; and R18Ais hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, or optionally substituted C3-8cycloalkyl. The Plk4 inhibitor may be, e.g., a compound of formula (VII): or a pharmaceutically acceptable salt thereof; wherein n, A, L, R15A, R15B, RA’, RA”, RL, R17, and R18are as defined in formula (VI). The Plk4 inhibitor may be, e.g., a compound of formula (VIII): or a pharmaceutically acceptable salt thereof; wherein n, A, L, R15A, R15B, RA, RA", RL, R17, and R18are as defined in formula (VI).

[0287] The Plk4 inhibitor may be, e.g., a compound of formula (Vll-A): or a pharmaceutically acceptable salt thereof; wherein n, L, R15A, R15B, RA", RL, R17, and R18are as defined in formula (VI).

[0288] The Plk4 inhibitor may be, e.g., a compound of formula (Vlll-A):

[0289] (Vlll-A), or a pharmaceutically acceptable salt thereof; wherein n, L, R15A, R15B, RA", RL, R16, R17, and R18are as defined in formula (VI).

[0290] The Plk4 inhibitor may be, e.g., a compound of formula (Vll-B): or a pharmaceutically acceptable salt thereof; wherein n, L, R15A, R15B, RA, RA", RL, R17, and R18are as defined in formula (VI). The Plk4 inhibitor may be, e.g., a compound of formula (Vlll-B):

[0291] (Vlll-B), or a pharmaceutically acceptable salt thereof; wherein n, L, R15A, R15B, RA, RA", RL, R16, R17, and R18are as defined in formula (VI). The Plk4 inhibitor may be, e.g., a compound of formula (Vll-C): or a pharmaceutically acceptable salt thereof wherein n, L, R15A, R15B, RL, R17, and R18are as defined in formula (VI). The Plk4 inhibitor may be, e.g., a compound of formula (Vlll-C):

[0292] (Vlll-C) or a pharmaceutically acceptable salt thereof wherein n, L, R15A, R15B, RL, R16, R17, and R1800are as defined in formula (VI). The Plk4 inhibitor may be, e.g., a compound of formula (Vll-D): or a pharmaceutically acceptable salt thereof wherein n, L, R15A, R15B, RL, R17, and R18are as defined in formula (VI). The Plk4 inhibitor may be, e.g., a compound of formula (Vlll-D):

[0293] (Vlll-D), or a pharmaceutically acceptable salt thereof wherein n, L, R15A, R15B, RL, R16, R17, and R18are as defined in formula (VI). The Plk4 inhibitor may be, e.g., a compound listed in Table 3 or a pharmaceutically acceptable salt thereof. Table 3 Further, non-limiting examples of Plk4 inhibitors include centrinone (CAS No.: 1798871-31-4), CFI-400945 (CAS No.: 1338806-73-7), and pharmaceutically acceptable salts thereof. Additional non- limiting examples of Plk4 inhibitors are also disclosed in US 10,752,612; US 20190070190; US 20200383990; and WO 2023159307; the Plk4 inhibitors disclosed therein are incorporated herein by reference in their entirety. Rrm1 and Rrm2 Inhibitors Rrm1 inhibitors may be compounds that upon contacting Rrm1, whether in vitro, in cell culture, or in an animal, reduces the activity of Rrm1, such that the measured Rrm1 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Rrm1 inhibitors, Rrm1 IC50may 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, Rrm1 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). Rrm2 inhibitors may be compounds that upon contacting Rrm2, whether in vitro, in cell culture, or in an animal, reduce the activity of Rrm2, such that the measured Rrm2 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Rrm2 inhibitors, Rrm2 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, Rrm2 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). Examples of Rrm2 inhibitors are: motexafin gadolinium (CAS No.: 156436-89-4), hydroxyurea (CAS No.: 127-07-1), fludarabine (CAS No.: 75607-67-9), cladribine (CAS No.: 4291-63-8), tezacitabine (CAS No.: 171176-43-5), triapine (CAS No.: 143621-35-6), and pharmaceutically acceptable salts thereof. Exemplary Rrm2 inhibitors are also disclosed in US 4,188,378; US 4,357,324; and US 2019 / 0161461; the Rrm2 inhibitors disclosed therein are incorporated herein by reference in their entirety. Sae1 Inhibitors Sae1 inhibitors may be compounds that upon contacting Sae1, whether in vitro, in cell culture, or in an animal, reduce the activity of Sae1, such that the measured Sae1 IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Sae1 inhibitors, Sae1 IC50may 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, Sae1 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). Examples of Sae1 inhibitors are: ML792 (CAS No.: 1644342-14-2) and pharmaceutically acceptable salts thereof. Exemplary Sae1 inhibitors are also disclosed in US 7,951,810; US 8,008,307; US 8,207,177; US 9,683,003; and US 9,695,154; the Sae1 inhibitors disclosed therein are incorporated herein by reference in their entirety. Sod1 Inhibitors Sod1 inhibitors may be compounds that upon contacting Sod1, whether in vitro, in cell culture, or in an animal, reduce the activity of Sod1, such that the measured Sod1 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Sod1 inhibitors, Sod1 IC50may 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, Sod1 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). Examples of Sod1 inhibitors are: LCS1 (CAS No.: 41931-13-9), ATN-224 (CAS No.: 649749-10-0), pyrimethamine (CAS No.: 58-14-0), and pharmaceutically acceptable salts thereof. Sod2 Inhibitors Sod2 inhibitors may be compounds that upon contacting Sod2, whether in vitro, in cell culture, or in an animal, reduce the activity of Sod2, such that the measured Sod2 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Sod2 inhibitors, Sod2 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, Sod2 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). Examples of Sod2 inhibitors are: LCS1 (CAS No.: 41931-13-9), ATN-224 (CAS No.: 649749-10-0), pyrimethamine (CAS No.: 58-14-0), and pharmaceutically acceptable salts thereof. Top1 Inhibitors Top1 inhibitors may be compounds that upon contacting Top1, whether in vitro, in cell culture, or in an animal, reduce the activity of Top1, such that the measured Top1 IC50 is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Top1 inhibitors, Top1 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, Top1 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). Examples of Top1 inhibitors are: irinotecan (CAS No.: 97682-44-5) (including its metabolite irino metab), topotecan (CAS No.: 123948-87-8), camptothecin (CAS No.: 7689-03-4), lamellarin D (97614-65-9), and pharmaceutically acceptable salts thereof. Exemplary Top1 inhibitors are also disclosed in US 4,604,463; US 4,894,456; and US 5,004,758; the Top1 inhibitors disclosed therein are incorporated herein by reference in their entirety. Top2 Inhibitors Top2 inhibitors may be compounds that upon contacting Top2, whether in vitro, in cell culture, or in an animal, reduce the activity of Top2, such that the measured Top2 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Top2 inhibitors, Top2 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, Top2 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). Examples of Top2 inhibitors are: etoposide (CAS No.: 33419-42-0), teniposide (CAS No.: 29767-20-2), doxorubicin (CAS No.: 23214-92-8), daunorubicin (CAS No.: 20830-81-3), mitoxantrone (CAS No.: 65271-80-9), amsacrine (CAS No.: 51264-14-3), ellipticine (CAS No.: 519-23-3), and pharmaceutically acceptable salts thereof. Exemplary Top2 inhibitors are also disclosed in US 3,590,028; US 3,933,827; US 3,989,598; US 4,258,191; US 4,464,529; and US 4,965,348; the Top2 inhibitors disclosed therein are incorporated herein by reference in their entirety. Ttk Inhibitors Ttk inhibitors may be compounds that upon contacting Ttk, whether in vitro, in cell culture, or in an animal, reduce the activity of Ttk, such that the measured Ttk IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Ttk inhibitors, Ttk 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, Ttk 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). Examples of Ttk inhibitors are: BAY1217389 (CAS No.: 1554458-53-5) and pharmaceutically acceptable salts thereof. Exemplary Ttk inhibitors are also disclosed in US 8,551,980; US 8,729,082; US 9,199,999; US 9,212,184; US 9,284,317; US 9,340,528; US 9,388,140; US 9,388,177; US 9,468,642; US 9,512,126; US 9,512,130; US 9,555,022; US 9,586,958; US 9,663,510; US 9,670,202; US 2017 / 0217946; US 2017 / 0305912; US 2017 / 0334899; US 2017 / 0342064; US 9,676,766; Wengner et al., Mol. Cancer Ther., 15:583-592, 2016; Zaman et al., Mol. Cancer Ther., 16:2609-2617, 2017; Mason et al., Proc. Nat’l Acad. Sci. U.S.A., 21:3127-3132, 2017; and Riggs et al., J. Med. Chem., 62:4401-4410, 2019; the Ttk inhibitors disclosed therein are incorporated herein by reference in their entirety. Uba2 Inhibitors Uba2 inhibitors may be compounds that upon contacting Uba2, whether in vitro, in cell culture, or in an animal, reduce the activity of Uba2, such that the measured Uba2 IC50is 10 µM or less (e.g., 5 µM or less or 1 µM or less). For certain Uba2 inhibitors, Uba2 IC50may 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, Uba2 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). Examples of Uba2 inhibitors are: TAK981 (CAS No.: 1858276-04-6) and pharmaceutically acceptable salts thereof. Exemplary Uba2 inhibitors are also disclosed in US 9,045,483; the Uba2 inhibitors disclosed therein are incorporated herein by reference in their entirety. Wee1 Inhibitors Wee1 inhibitors may be compounds that upon contacting Wee1, whether in vitro, in cell culture, or in an animal, reduce the activity of Wee1, such that the measured 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 10 pM. Preferably, Wee1 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). Examples of Wee1 inhibitors are: Adavosterib Azenosterib WO2020192581 Example 59 , and pharmaceutically acceptable salts thereof. Further Examples of Wee1 inhibitors can be found in, e.g., US Patent Nos.: 8,710,065; 8,716,297; 8,791,125, 9,181,239; 9,850,247; 11,332,473; 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 are all incorporated herein by reference in their entirety. Platinum-Based DNA-Damaging Agent Platinum-based DNA-damaging agents are coordination compounds of Pt(II) or Pt(IV), typically known in the art as platins. Platinum-based DNA-damaging agents include at least two coordination sites at the platinum center that are occupied by nitrogenous spectator ligand(s). The nitrogenous spectator ligands are monodentate or bidentate ligands, in which the donor atom(s) is an sp3- or sp2-hybridized nitrogen atom within the ligand. Non-limiting examples of nitrogenous spectator ligands are ammonia, 1,2-cyclohexanediamine, a picoline, phenanthrin, or 1,6-hexanediamine. Non-limiting examples of platinum-based DNA-damaging agents include cisplatin (CAS No.: 15663-27-1), carboplatin (CAS No.: 41575-94-4), oxaliplatin (CAS No.: 63121-00-6), nedaplatin (CAS No.: 95734-82-0), triplatin tetranitrate (CAS No.: 172903-00-3), phenanthriplatin (CAS No.: 66-71-7), picoplatin (CAS No.: 181630-15-9), and satraplatin (CAS No.: 129580-63-8). Methods Of Treatment

[0294] Methods disclosed herein may be used for the treatment of a cancer, e.g., a cancer with a replication stress biomarker. Methods disclosed herein may include the step of administering to the subject in need thereof a therapeutically effective amount of a membrane-associated tyrosine and threonine-specific cdc2 inhibitory kinase (Myt1) inhibitor and a therapeutically effective amount of a second therapeutic. The second therapeutic may be, e.g., Wee1 inhibitor, Fen1 inhibitor, Topi inhibitor, Rrm1 inhibitor, Rrm2 inhibitor, Aurkb inhibitor, Top2A inhibitor, Atr inhibitor, Ttk inhibitor, Sod1 inhibitor, Sod2 inhibitor, Bub1 inhibitor, Cdc7 inhibitor, Sae1 inhibitor, Plk1 inhibitor, Uba2 inhibitor, Dut inhibitor, Hdac3 inhibitor, Chekl inhibitor, Aurka inhibitor, Men1 inhibitor, Doti I inhibitor, Crebbp inhibitor, Ezh2 inhibitor, Plk4 inhibitor, Haspin inhibitor, Mettl3 inhibitor, nucleoside analog, platinum-based DNA damaging agent, or a combination thereof.

[0295] The cancer may have or be characterized by a replication stress biomarker. Administration of a Myt1 inhibitor to a subject with a cancer which has been previously identified to include a replication stress biomarker, or a cancer known to have a replication stress biomarker, may increase the replication stress of the cancer cell. The combination of a replication stress biomarker and a replication stress inducing therapeutic (such as Myt1) may result in premature mitosis of a cell, resulting in a daughter cell or daughter cells which may be unviable (e.g., due to induced DNA breaks or chromosome pulverization), ultimately resulting in the death of the cancer cell. In some embodiment, the replication stress of the cancer cell may be increased by administering a second therapeutic (e.g., a Wee1 inhibitor, a Fen1 inhibitor, a Topi inhibitor, an Rrm1 inhibitor, an Rrm2 inhibitor, an Aurkb inhibitor, a Top2A inhibitor, an Atr inhibitor, a Ttk inhibitor, an Sod1 inhibitor, an Sod2 inhibitor, a Bub1 inhibitor, a Cdc7 inhibitor, an Sae1 inhibitor, a Plk1 inhibitor, a Uba2 inhibitor, a Dut inhibitor, an Hdac3 inhibitor, a Chekl inhibitor, an Aurka inhibitor, a Men1 inhibitor, a Doti I inhibitor, a Crebbp inhibitor, an Ezh2 inhibitor, a Plk4 inhibitor, an Haspin inhibitor, a Mettl3 inhibitor, a nucleoside analog, a platinum-based DNA damaging agent, or a combination thereof). The replication stress biomarker may be a mutation (i.e., a gain-of-function mutation or a loss-of-function mutation) or gene amplification of a gene associated with replication stress. The replication stress biomarker may be a mutation (i.e., a gain-of-function mutation or a loss-of-function mutation) or gene amplification of e.g., a mutation or gene amplification of KRAS, NRAS, HRAS, TP53, CCNE1, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, FBXW7, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, ARAF, BRAF, CRAF, a prior or current infection with HPV, or a combination thereof. In some embodiments, the cancer may have more than one replication stress biomarker (e.g., mutations to genes encoding different isoforms of a protein, a mutation to more than one gene in a family, more than one mutation in the same gene, a concurrent gain-of-function mutation and gene amplification of a gene, a mutation to two different genes, etc.).

[0296] In some embodiments, the replication stress biomarker the cancer is associated with is a RAS mutation or RAS amplification. Cancers associated with RAS mutation or RAS amplification include, e.g., uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, and endometrial cancer. In embodiments wherein the RAS mutation is a KRAS mutation, the cancer is preferably colorectal cancer, pancreatic cancer, lung cancer, a gynecological cancer (e.g., uterine cancer, ovarian cancer, cervical cancer), or gastro-esophageal cancers. In embodiments wherein the RAS mutation is a HRAS mutation, the cancer is preferably thyroid cancer, kidney cancer, bladder cancer, or a head and neck cancer. In embodiments wherein the RAS mutation is an NRAS mutation, the cancer is preferably a colorectal cancer or a melanoma. In some embodiments, the cancer is associated with RAS amplification. In some embodiments, the cancer is associated with KRAS amplification.

[0297] In some embodiments, the replication stress biomarker the cancer is associated with is a TP53 mutation. Cancers associated with TP53 mutations include ovarian cancer, esophageal cancer, colorectal cancer, head and neck cancer, and lung cancer.

[0298] In some embodiments, the replication stress biomarker the cancer is associated with is CCNE1 amplification. Cancers associated with CCNE1 amplification include uterine cancer, ovarian cancer, pancreatic cancer, mesothelioma, kidney cancer, bladder cancer, gastric cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, and endometrial cancer.

[0299] In some embodiments, the replication stress biomarker the cancer is associated with is a CDK mutation or a mutation to a gene encoding a CDK regulatory protein. Cancers associated with a CDK mutation or a mutation to a gene encoding a CDK regulatory protein include bladder cancer, melanoma, breast cancer, colorectal cancer, pancreatic cancer, lung cancer, cervical cancer, and ovarian cancer.

[0300] In some embodiments, the replication stress biomarker the cancer is associated with is a EGFR mutation. Cancers associated with EGFR mutations include lung cancer.

[0301] In some embodiments, the replication stress biomarker the cancer is associated with is a FBXW7 mutation. Cancers associated with FBXW7 include uterine cancer, ovarian cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer.

[0302] In some embodiments, the replication stress biomarker the cancer is associated with is a c-MYC mutation or c-MYC amplification. Cancers associated with c-MYC mutations and amplification include ovarian cancer, lung cancer, breast cancer, liver cancer, colorectal cancer, and prostate cancer.

[0303] In some embodiments, the replication stress biomarker the cancer is associated with is a PIK3CA mutation. Cancers associated with PIK3CA mutations include breast cancer, ovarian cancer, colorectal cancer, ovarian cancer, breast cancer, brain cancer, liver cancer, stomach cancer, and lung cancer.

[0304] In some embodiments, the replication stress biomarker the cancer is associated with is a PPP2R1A mutation. Cancers associated with PPP2R1A mutations include endometrial cancer, ovarian cancer, and uterine cancer.

[0305] In some embodiments, the replication stress biomarker the cancer is associated with is a PTEN mutation. Cancers associated with PTEN mutations include breast cancer, prostate cancer, bladder cancer, lung cancer, endometrial cancer, lung cancer, melanoma, and head and neck cancer.

[0306] In some embodiments, the replication stress biomarker the cancer is associated with is a RB1 mutation. Cancers associated with RB1 mutations include brain cancer, bone cancer, muscle cancer, prostate cancer, uterine cancer, breast cancer, lung cancer, and melanoma.

[0307] In some embodiments, the replication stress biomarker the cancer is associated with is a BRAF mutation. Cancers associated with BRAF mutations include melanoma, leukemia, lymphoma, and lung cancer.

[0308] In some embodiments, the replication stress biomarker the cancer is associated with is a prior infection with HPV. Cancers associated with HPV infection include cervical cancer, penile cancer, vaginal cancer, vulvar cancer, colorectal cancer, and throat cancer. Compounds disclosed herein 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.

[0309] In some embodiments, the Myt1 inhibitor is administered before the second agent (e.g., within 1 week, within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, or within 12 hours). In some embodiments, the Myt1 inhibitor is administered after the second agent (e.g., within 1 week, within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, or within 12 hours). In some embodiments, the Myt1 inhibitor is co-administered with the second agent. In some embodiments, the Myt1 inhibitor is administered intermittently (e.g., 1 day / week, 2 days / week, or 3 days / week). In some embodiments, the second agent is administered on a continuous daily basis.

[0310] Pharmaceutical Compositions

[0311] The compounds used in the methods described herein are preferably 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 may include one or more additional pharmaceutically active agents described herein.

[0312] 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 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, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0313] 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 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.

[0314] This invention also includes methods of administering pharmaceutical compositions which can contain one or more 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 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.

[0315] The excipient or carrier is selected on the basis of the mode and route of administration. Suitable 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, 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 al., Eds., Pharmaceutical Press (2009).

[0316] 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., 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 other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of 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.

[0317] Dosages

[0318] 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 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 some embodiments, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. In some embodiments, an effective dose is a subtherapeutic dose relative to the monotherapy. Such an effective dose will generally depend upon the factors described above.

[0319] A compound of the invention may be administered to the patient in a single dose or in multiple doses. When multiple doses are administered, the doses may be separated from one another by, for example, 1-24 hours, 1-7 days, 1-4 weeks, or 1-12 months. The compound may be administered according to a schedule or the compound may be administered without a predetermined schedule. An active compound may be administered, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times per day, every 2nd, 3rd, 4th, 5th, or 6th day, 1 , 2, 3, 4, 5, 6, or 7 times per week, 1 , 2, 3, 4, 5, or 6 times per month, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times per year. It is to be understood that, for any particular subject, specific dosage regimes should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0320] While the attending physician ultimately will decide the appropriate amount and dosage regimen, an effective amount of a compound of the invention may be, for example, a total daily dosage of, e.g., between 0.05 mg and 3000 mg of any of the compounds described herein. Alternatively, the dosage amount can be calculated using the body weight of the patient. Such dose ranges may include, for example, between 10-1000 mg (e.g., 50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.

[0321] In the methods of the invention, the time period during which multiple doses of a compound of the invention are administered to a patient can vary. For example, in some embodiments, doses of the compounds of the invention are administered to a patient over a time period that is 1-7 days; 1-12 weeks; or 1-3 months. In some embodiments, the compounds are administered to the patient over a time period that is, for example, 4-11 months or 1-30 years. In some embodiments, the compounds are administered to a patient at the onset of symptoms. In any of these embodiments, the amount of compound that is administered may vary during the time period of administration. When a compound is administered daily, administration may occur, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 times per day.

[0322] Formulations

[0323] A compound identified as capable of treating any of the conditions described herein, using 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 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 disease or condition. Administration may begin before the patient is symptomatic.

[0324] Exemplary routes of administration of the compounds (e.g., a compound 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 formulated for treatment of the disorders described herein are also part of the present invention.

[0325] Formulations for Oral Administration

[0326] 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 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 agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato 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 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.

[0327] Formulations for oral administration may also be presented as chewable tablets, as hard gelatin capsules where 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 where the active ingredient is mixed with water or an oil medium, for example, peanut oil, 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.

[0328] 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 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, and liposomes. In some embodiments, compositions include biodegradable, pH, and / or temperature-sensitive polymer coatings.

[0329] 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 mentioned above and / or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl 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 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.

[0330] 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 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.

[0331] Formulations for Parenteral Administration

[0332] 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 described herein. The pharmaceutical formulation may also be administered parenterally (intravenous, intramuscular, subcutaneous or the like) in dosage forms or formulations containing conventional, nontoxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation 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 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.

[0333] The parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration:

[0334] (1) Drug Injection: a liquid preparation that is a drug substance (e.g., a compound of the invention), or a solution thereof;

[0335] (2) Drug for Injection: the drug substance (e.g., a compound of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection;

[0336] (3) Drug Injectable Emulsion: a liquid preparation of the drug substance (e.g., a compound of the invention) that is dissolved or dispersed in a suitable emulsion medium;

[0337] (4) Drug Injectable Suspension: a liquid preparation of the drug substance (e.g., a compound of the invention) suspended in a suitable liquid medium; and

[0338] (5) Drug for Injectable Suspension: the drug substance (e.g., a compound of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injectable suspension.

[0339] 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 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, 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 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.

[0340] 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: aqueous solutions, powders for reconstitution, cosolvent solutions, oil / water emulsions, suspensions, oilbased solutions, liposomes, microspheres, and polymeric gels.

[0341] EXAMPLES

[0342] The following examples were meant to illustrate the invention. They were not meant to limit the invention in any way.

[0343] Methods

[0344] KRAS / TP53 double mutant isogenic cell pairs, across relevant tumor origins, were genetically engineered to express a KRAS gain-of-function mutant codon and allele (resulting in amino acid substitutions G12D, G12C, G12V, G12R, G13D and Q61 H). Cell cycle distribution perturbations and replication stress were evaluated. Sensitivity to representative Myt1 inhibitors (e.g., compound 182) alone or in combination with chemotherapeutic or targeted agents was assessed by cell growth assays. In vitro findings were further evaluated in KRAS / TP53 double mutant patient-derived xenografts (PDX). Response to treatment may be measured by, e.g., tumor volume, cell lethality (and its converse, cell viability), confluence of a culture dish, synergistic area score, tumor growth inhibition (TGI; the relative change in tumor volume between a measured population vs a control), or the fold shift in treatment efficacy relative to a wild-type cell.

[0345] Example 1 : Treatment of KRAS-Mutated Cancers with Myt1 inhibitors

[0346] KRAS-mutated cancers are commonly observed to be resistant to chemotherapeutic treatments. However, chemotherapeutic treatment with further drivers of replication stress (e.g., Myt1 inhibitors) may lead to a dose dependent chemotherapeutic response.

[0347] Two strains of isogenic KRAS-mutated lung cells (BRONCH2 TP53AQ61 H B4 and BRONCH2 TP53AG12C E12) were treated with a variable dose of representative Myt1 inhibitor compound 182 (see FIG. 1A and FIG. 1 B, respectively), and compared with treatment the wild type cell. In both experiments, a notable decrease in confluence (i.e., increased lethality) is observed at ~4-12x lower concentration of compound 182 in KRAS-mutated cells as compared to wild type.

[0348] These results were confirmed in several other KRAS mutant cell lines. The results are summarized in Table 4. Table 4. Treatment of KRAS-Mutant Cancer Cells with Myt1 Inhibitor Monotherapy

[0349] This example demonstrates that Myt1 inhibitors are capable of driving cell death in KRAS mutant cancer cells when administered as a monotherapy.

[0350] Example 2: Myt1 Inhibitor Combination Therapies Driving Replication Stress

[0351] Combination therapies including a Myt1 inhibitor and replication-stress inducing therapeutic agents (nucleoside analogs, platinum salts, Topi inhibitors, Atr inhibitors) for treating KRAS mutations were investigated. It is hypothesized that a combination of Myt1 inhibitors with these agents would further exacerbate the replication stress in KRAS- and 7P53-mutated cancer cells and therefore synergize to decrease cell viability and increase treatment lethality.

[0352] Combination therapies to treat various cell lines were therefore investigated. The most synergistic area scores (score >10 indicates synergy) for exemplary combination therapies using Compound 182 and a combination partner are summarized in Table 5. Table 5. Treatment of KRAS-Mutant Cancers in Myt1 Inhibitor Combination Therapies

[0353] These experiments demonstrate the applicability of combination therapies of Myt1 inhibitors with a second therapeutic agents for treating a variety of KRAS mutant cancers. Of note is the combination of compound 182 and camonsertib, which exhibits high synergy across all measurements.

[0354] Example 3: Myt1 Inhibitor / Nucleoside-Analog Combination Therapies Driving Replication Stress

[0355] Combination therapies including a Myt1 inhibitor and a nucleoside-analogs for treating KRAS mutations were investigated. As indicated by the results of Example 2, a combination therapy including a Myt1 inhibitor and a nucleoside analog may be an effective therapy for the treatment of a KRAS mutant cancer.

[0356] Gemcitabine (a representative nucleoside analog) and compound 182 (a representative Myt1 inhibitor) were administered in a combination therapy to determine if such a synergistic effect was noted. 62.5 nM of compound 182 was administered in combination with one of two concentrations of Gemcitabine (either 0.625 nM or 1 .3 nM) to one of three isogenic cell lines expressing wild type KRAS (BRONCH2 TP53 / _WT, FIG. 2A), Q61 H mutated KRAS (BRONCH2 TP53Z- Q61 H, FIG. 2B), or G12C mutated KRAS (BRONCH2 TP53Z- G12C, FIG. 2C). As FIG. 2A shows, the viability of WT Kras cells is minimally impacted by treating with gemcitabine and compound 182, alone or in combination, at both observed concentrations of gemcitabine. As FIG. 2B shows, the viability of Q61 H-mutated Kras cells is modestly reduced when treated with gemcitabine alone (>99% viability at 0.625 nM of gemcitabine and 20% at 1.3 nM of gemcitabine) and compound 182 alone (~90% viability). The viability of Q61 H-mutated Kras cells is greatly reduced when treated with the combination therapy (~26% viability at 0.625 nM of gemcitabine and ~3% at 1.3 nM of gemcitabine). As FIG. 2C shows, the viability of G12C mutated Kras is slightly reduced when treated with gemcitabine alone (>99% viability at 0.625 nM of gemcitabine and ~90% at 1.3 nM of gemcitabine) and compound 182 alone (90% viability). The viability of G12C mutated cancers is greatly reduced when treated with the combination of gemcitabine and compound 182 (~50% viability at 0.625 nM of gemcitabine and ~5% at 1.3 nM of gemcitabine).

[0357] To the synergistic efficacy of combinations of compound 182 with gemcitabine was further confirmed in mouse patient-derived xenograft (PDX) models of pancreatic cancer (FIG. 3A-C). In all three models, the combination of twice-daily (BID) compound 182 dosed at 10 mg / kg with once-weekly 20 mg / kg gemcitabine resulted in significant anti-tumor activity, including durable tumor regressions in 2 / 3 models (FIG. 3A-C). In each case the combination outperformed single-agent efficacy (FIG. 3A-C).

[0358] The above experiments demonstrate the effective combination therapeutic treatment of KRAS- mutated cancers.

[0359] Example 4: Myt1 Inhibitor / Atr Inhibitor Combination Therapies Driving Replication Stress

[0360] Combination therapies including a Myt1 inhibitor and an Atr inhibitor for treating Kras mutations were investigated. Atr kinase is activated in cells under replication stress, reducing the potential lethality to the cell. Therefore, simultaneous administration of a Myt1 inhibitor with an Atr inhibitor to treat a cancer with a replication stress mutation (e.g., a Kras mutation) may synergize to decrease cell viability and increase treatment lethality.

[0361] Combination therapies using representative Myt1 inhibitor compound 182 and representative Atr inhibitor camonsertib were investigated in four colorectal PDX models: CR3262 (G12D Kras mutation; FIG. 4A), CR3150 (G12V Kras mutation; FIG. 4B), CR3099 (G12D Kras mutation; FIG. 4C), and CR3820 (G12D mutation; FIG. 4D). Tumor growth in each PDX model was monitored in the presence of (1) the vehicle alone; (2) a 5 mg / kg dose of compound 182 (twice daily) as a monotherapy; (3) a 10 mg / kg dose of camonsertib (3-days-on-4-days-off dosing schedule) as a monotherapy; and (4) the combination therapy of compound 182 (5 mg / kg; twice daily) and camonsertib (10 mg / kg; 3-days-on-4-days-off dosing schedule). Each therapy was tested on a group of 5 mice. Significant reduction in tumor growth was observed for CR3150 (G12V), CR3099 (G12D), and CR3820 (G12D) (TGI = 88%, 89%, and 97% respectively), with a smaller reduction in tumor growth observed for CR3262 (G12D) (TGI = 40-44%). Further, the combination was well tolerated - with only one mouse in 3 of the four groups requiring a dosing holiday.

[0362] This example demonstrates that a combination therapy including a Myt1 inhibitor and an Atr inhibitor is highly effective at treating KRAS mutated caners. Such a combination therapy exhibited a high response rate and was generally well tolerated. ENUMERATED EMBODIMENTS

[0363] E1 . A method for treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a membrane-associated tyrosine and threonine-specific cdc2-inhibatory kinase (Myt1) inhibitor, wherein the cancer comprises a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAE, or a prior or current infection with HPV.

[0364] E2. A method for treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a membrane-associated tyrosine and threonine-specific cdc2-inhibatory kinase (Myt1) inhibitor, wherein the cancer comprises a cancer previously identified as a cancer comprising a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

[0365] E3. A method of inducing death in a cancer cell, the method comprising contacting the cell with an effective amount of a Myt1 inhibitor, wherein the cancer comprises a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

[0366] E4. A method of inducing death in a cancer cell, the method comprising contacting the cell with an effective amount of a Myt1 inhibitor, wherein the cancer comprises a cancer previously identified as a cancer comprising a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

[0367] E5. The method of any one of claims E1 to E4, wherein the cancer comprises a KRAS mutation.

[0368] E6. The method of claim E5, wherein the KRAS mutation encodes for an amino acid substitution in a Kras protein, wherein the amino acid substitution is G12D, G12V, G12C, G13D, G12R, G12A, Q61 H, G12S, A146T, G13C, Q61 L, Q61 R, K117N, A146V, G12F, Q61 K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, or combinations thereof.

[0369] E7. The method of claim E5 or claim E6, wherein the cancer comprises colorectal cancer, pancreatic cancer, lung cancer, uterine cancers, ovarian cancer, cervical cancer or gastro-esophageal cancer.

[0370] E8. The method of any one of claims E1 to E4, wherein the cancer comprises KRAS amplification.

[0371] E9. The method of any one of claims E1 to E4, wherein the cancer comprises a HRAS mutation.

[0372] E10. The method of claim E9, wherein the HRAS mutation encodes for an amino acid substitution in a Hras protein, wherein the amino acid substitution is Q61 R, G13R, Q61 K, G12S, Q61 L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61 H, G13S, A18V, D119N, G13N,

[0373] A146T, A66T, G12A, A146V, G12N, or G12R, or combinations thereof.

[0374] E11 . The method of claim E9 or claim E10, wherein the cancer comprises kidney cancer, bladder cancer, head and neck cancer, or thyroid cancer.

[0375] E12. The method of any one of claims E1 to E4, wherein the cancer comprises a NRAS mutation.

[0376] E13. The method of claim E12, wherein the NRAS mutation encodes for an amino acid substitution in a Nras protein, wherein the amino acid substitution is Q61 R, Q61 K, G12D, Q61 L, Q61 H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61 P, A59D, E132K, E49K, T50I, A146V, orA59T, or combinations thereof.

[0377] E14. The method of claim E12 or claim E13, wherein the cancer comprises colorectal cancer, thyroid cancer, or melanoma.

[0378] E15. The method of any one of claims E5 to E14, wherein the cancer further comprises a TP53 mutation.

[0379] E16. The method of any one of claims E1 to E4, wherein the cancer is uterine cancer, ovarian cancer, cervical cancer, bladder cancer, brain cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, head and neck cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, thyroid cancer, melanoma, or endometrial cancer.

[0380] E17. The method of any one of claims E1 to E16, further comprising administration of a therapeutically effective amount of a Wee1 inhibitor, Fen1 inhibitor, Topi inhibitor, Rrm1 inhibitor, Rrm2 inhibitor, Aurkb inhibitor, Top2A inhibitor, Atr inhibitor, Ttk inhibitor, Sod1 inhibitor, Sod2 inhibitor, Bub1 inhibitor, Cdc7 inhibitor, Sae1 inhibitor, Plk1 inhibitor, Uba2 inhibitor, Dut inhibitor, Hdac3 inhibitor, Chekl inhibitor, Aurka inhibitor, Men1 inhibitor, Doti I inhibitor, Crebbp inhibitor, Ezh2 inhibitor, Plk4 inhibitor, Haspin inhibitor, Mettl3 inhibitor, nucleoside analog, platinum-based DNA damaging agent, or a combination thereof.

[0381] E18. The method of any one of claims E1 to E17, wherein the method comprises the step of administering the Wee1 inhibitor.

[0382] E19. The method of claim 18, wherein the Wee1 inhibitor is one of:

[0383] E20. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Fen1 inhibitor.

[0384] E21. The method of claim E20, wherein the Fen1 inhibitor is C8 (PMID: 32719125), SC13, Fen1-IN-3, or a pharmaceutically acceptable salt thereof.

[0385] E22. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Topi inhibitor.

[0386] E23. The method of claim E22, wherein the Topi inhibitor is irinotecan, topotecan, camptothecin, lamellarin D, or a pharmaceutically acceptable salt thereof.

[0387] E24. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Rrm1 inhibitor.

[0388] E25. The method of any one of claims E1 to E24, wherein the method comprises the step of administering the Rrm2 inhibitor.

[0389] E26. The method of claim E25, wherein the Rrm2 inhibitor is motexafin gadolinium, hydroxyurea, fludarabine, cladribine, tezacitabine, triapine, or a pharmaceutically acceptable salt thereof.

[0390] E27. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Aurkb inhibitor.

[0391] E28. The method of claim E27, wherein the Aurkb inhibitor is MK-0457, AZD1152, PHA739358, AT9283, AMG900, SNS-314, TAK-901 , CYC116, GSK1070916, PF03814735, or a pharmaceutically acceptable salt thereof.

[0392] E29. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Top2A inhibitor.

[0393] E30. The method of claim E29, wherein the Top2A inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, or a pharmaceutically acceptable salt thereof.

[0394] E31 . The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Atr inhibitor.

[0395] E32. The method of claim E31 , wherein the Atr inhibitor is a compound of formula (IV): (IV), or a pharmaceutically acceptable salt thereof, wherein is a double bond, and each Y is independently N or CR4; or is a single bond, and each Y is independently NRY, carbonyl, or C(RY)2; wherein each RYis independently H or optionally substituted C1-6 alkyl; R1is optionally substituted C1-6alkyl or H; R2is optionally substituted C2-9heterocyclyl, optionally substituted C1-6alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6- 10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, –N(R5)2, –OR5, –CON(R6)2, –SO2N(R6)2,–SO2R5A, or –Q–R5B; R3is optionally substituted C1-9heteroaryl or optionally substituted C1-9heteroaryl C1-6alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9heteroaryl, or –SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, or optionally substituted C6-10aryl; R5Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, –N(R5)2, –CON(R6)2, –SO2N(R6)2, –SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9heterocyclyl; Q is optionally substituted C2-9heterocyclylene, optionally substituted C3-8cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; and X is hydrogen or halogen. E33. The method of claim E31, wherein the Atr inhibitor is a compound of formula (V): (V), or a pharmaceutically acceptable salt thereof, wherein each Y is independently N or CR4; R1is optionally substituted C1-6 alkyl or H; R2is optionally substituted C2-9heterocyclyl, optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-9heterocyclyl C1-6alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, –N(R5)2, –OR5, –CON(R6)2, –SO2N(R6)2,–SO2R5A, or –Q–R5B; R3is optionally substituted C1-9heteroaryl or optionally substituted C1-9heteroaryl C1-6alkyl; each R4is independently hydrogen, halogen, optionally substituted C1-6alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R5is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9heteroaryl, or –SO2R5A; or both R5, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R5Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10aryl; R5Bis hydroxyl, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9 heteroaryl, –N(R5)2, –CON(R6)2, –SO2N(R6)2, –SO2R5A, or optionally substituted alkoxy; each R6is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkoxyalkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R6, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; Q is optionally substituted C2-9heterocyclylene, optionally substituted C3-8cycloalkylene, optionally substituted C1-9heteroarylene, or optionally substituted C6-10arylene; and X is hydrogen or halogen. E34. The method of any one of claim E31 to E33, wherein the Atr inhibitor is selected from the group consisting of compounds A43, A57, A62, A87, A93, A94, A95, A99, A100, A106, A107, A108, A109, A111, A112, A113, A114, A115, A116, A118, A119, A120, A121 (camonsertib), A122, A123, A135, A147, A148, and pharmaceutically acceptable salts thereof. E35. The method of any one of claims E31 to E34, wherein the Atr inhibitor is compound A43 or a pharmaceutically acceptable salt thereof.

[0396] E36. The method of any one of claims E31 to E34, wherein the Atr inhibitor is camonsertib or a pharmaceutically acceptable salt thereof.

[0397] E37. The method of any one of claims E31 to E34, wherein the Atr inhibitor is compound A122 or a pharmaceutically acceptable salt thereof.

[0398] E38. The method of claim E31 , wherein the Atr inhibitor is elimusertib (BAY1895344) ceralasertib (AZD6738) berzosertib (VE-822)

[0399] SKLB-197 or a pharmaceutically acceptable salt thereof.

[0400] E39. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Ttk inhibitor.

[0401] E40. The method of claim E39, wherein the Ttk inhibitor is BAY1217389 or a pharmaceutically acceptable salt thereof. E41 . The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Sod1 inhibitor.

[0402] E42. The method of claim E41 , wherein the Sod1 inhibitor is LCS1 , ATN-224, Pyrimethamine, a compound of the following structure or a pharmaceutically acceptable salt thereof.

[0403] E43. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Sod2 inhibitor.

[0404] E44. The method of claim E43, wherein the Sod2 inhibitor is LCS1 , ATN-224, pyrimethamine, or a pharmaceutically acceptable salt thereof.

[0405] E45. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Bub1 inhibitor.

[0406] E46. The method of claim E45, wherein the Bub1 inhibitor is BAY-320, BAY-419, BAY1816032, or a pharmaceutically acceptable salt thereof.

[0407] E47. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Cdc7 inhibitor.

[0408] E48. The method of claim E47, wherein the Cdc7 inhibitor is SRA141 , TAK931 , or a pharmaceutically acceptable salt thereof.

[0409] E49. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Sae1 inhibitor.

[0410] E50. The method of claim E49, wherein the Sae1 inhibitor is ML792 or a pharmaceutically acceptable salt thereof.

[0411] E51 . The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Plk1 inhibitor.

[0412] E52. The method of claim E51 , wherein the Plk1 inhibitor is BI2536, BI6727, TAK960, NMSP937, GSK461364, or a pharmaceutically acceptable salt thereof.

[0413] E53. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Uba2 inhibitor.

[0414] E54. The method of claim E53, wherein the Uba2 inhibitor is TAK981 or a pharmaceutically acceptable salt thereof.

[0415] E55. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Dut inhibitor.

[0416] E56. The method of claim E55, wherein the Dut inhibitor is TAS114 or a pharmaceutically acceptable salt thereof. E57. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Hdac3 inhibitor.

[0417] E58. The method of claim E57, wherein the Hdac3 inhibitor is RGFP966 or a pharmaceutically acceptable salt thereof.

[0418] E59. The method of any one of claims E1 to E16 wherein the method comprises the step of administering the Chekl inhibitor.

[0419] E60. The method of claim E59, wherein the Chekl inhibitor is SRA737 or a pharmaceutically acceptable salt thereof.

[0420] E61. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Aurka inhibitor.

[0421] E62. The method of claim E61 , wherein the Aurka inhibitor is MLN8237, MK-0457, MLN8054, PHA739358, AT9283, AMG900, MK5108, SNS314, TAK901 , CYC116, ENMD2076, or a pharmaceutically acceptable salt thereof.

[0422] E63. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Men1 inhibitor.

[0423] E64. The method of claim E63, wherein the Men1 inhibitor is MI3454, SNDX5613, VTP50469, KO539, or a pharmaceutically acceptable salt thereof.

[0424] E65. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Doti I inhibitor.

[0425] E66.The method of claim E65, wherein the Doti I inhibitor is EPZ5676 or a pharmaceutically acceptable salt thereof.

[0426] E67. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Crebbp inhibitor.

[0427] E68. The method of claim E67, wherein the Crebbp inhibitor is CPI4, CCS1477, E7386, NEO1132, NEO2734, PRI724, C82, BC001 , C646, EML425, CBP30, or a pharmaceutically acceptable salt thereof.

[0428] E69. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Ezh2 inhibitor.

[0429] E70. The method of claim E69, wherein the Ezh2 inhibitor is EPZ-6438, GSK126, or a pharmaceutically acceptable salt thereof.

[0430] E71. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Plk4 inhibitor.

[0431] E72. The method of claim E71 , wherein the Plk4 inhibitor is a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 , 2, 3, or 4; m is 0, 1 , or 2;

[0432] L is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted Ce-w aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of R3;

[0433] R1ais hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or nitrile;

[0434] R1bis hydrogen; or

[0435] R1aand R1b, together with the atoms to which they are attached, are a 3-5-membered cycloalkyl, cycloakylene, cycloalkylyne, heterocycloalkyl, aryl, or heteroaryl;

[0436] A is O or S, and R2Aand R2Bare both absent; or A is N, R2Ais absent, and R2Bis hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl, or R2Band L, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl or optionally substituted C2-9 heteroaryl; or A is C, and each of R2Aand R2Bare independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; each R3is independently halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, -S(O)mR3A, -N(R3B)2, or - OR3B;

[0437] R3Ais optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -OR3Bor -N(R3B)2 each R3Bis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; or two R3Bgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl; X is N, and R4is absent; or X is C, and R4is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;

[0438] R5is optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -CONH2, or -Z-R5A;

[0439] Z is optionally substituted amino, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, optionally substituted Cs-w arylene, or optionally substituted C3-8 cycloalkylene;

[0440] R5Ais hydrogen, halogen, cyano, optionally substituted C1-6 alkylsulfonyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;

[0441] R6is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or -OR6A; and

[0442] R6Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or optionally substituted C3-8 cycloalkyl.

[0443] E73. The method of claim E71 or claim E72, wherein the Plk4 inhibitor is a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 , 2, 3, or 4; m is 0, 1 , or 2;

[0444] L is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted Cs-w aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of R3;

[0445] R1ais hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or nitrile;

[0446] R1bis hydrogen; or R1aand R1b, together with the atoms to which they are attached, are a 3-5-membered cycloalkyl, cycloakylene, cycloalkylyne, heterocycloalkyl, aryl, or heteroaryl;

[0447] A is O or S, and R2Aand R2Bare both absent; or A is N, R2Ais absent, and R2Bis hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Ce-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl, or R2Band L, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl or optionally substituted C2-9 heteroaryl; or A is C, and each of R2Aand R2Bare independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; each R3is independently halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, -S(O)mR3A, -N(R3B)2, or - OR3B;

[0448] R3Ais optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -OR3Bor -N(R3B)2 each R3Bis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; or two R3Bgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl;

[0449] R5is optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -CONH2, or -Z-R5A;

[0450] Z is optionally substituted amino, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, optionally substituted Cs-w arylene, or optionally substituted C3-8 cycloalkylene;

[0451] R5Ais hydrogen, halogen, cyano, optionally substituted C1-6 alkylsulfonyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl; R6is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or -OR6A; and

[0452] R6Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or optionally substituted C3-8 cycloalkyl.

[0453] E74. The method of claim E71 or claim E72, wherein the Plk4 inhibitor is a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 , 2, 3, or 4; m is 0, 1 , or 2;

[0454] L is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted Cs-w aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of R3;

[0455] R1ais hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or nitrile;

[0456] R1bis hydrogen; or

[0457] R1aand R1b, together with the atoms to which they are attached, are a 3-5-membered cycloalkyl, cycloakylene, cycloalkylyne, heterocycloalkyl, aryl, or heteroaryl;

[0458] A is O or S, and R2Aand R2Bare both absent; or A is N, R2Ais absent, and R2Bis hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl, or R2Band L, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl or optionally substituted C2-9 heteroaryl; or A is C, and each of R2Aand R2Bare independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; each R3is independently halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, -S(O)mR3A, -N(R3B)2, or - OR3B;

[0459] R3Ais optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -OR3Bor -N(R3B)2 each R3Bis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; or two R3Bgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl;

[0460] R4is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;

[0461] R5is optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -CONH2, or -Z-R5A;

[0462] Z is optionally substituted amino, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, optionally substituted Cs-w arylene, or optionally substituted C3-8 cycloalkylene;

[0463] R5Ais hydrogen, halogen, cyano, optionally substituted C1-6 alkylsulfonyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;

[0464] R6is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or -OR6A; and

[0465] R6Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or optionally substituted C3-8 cycloalkyl.

[0466] E75. The method of any one of claims E71 to E74, wherein the Plk4 inhibitor is selected from the group consisting of compound P1 to P328.

[0467] E76. The method of claim E71 to E75, wherein the Plk4 inhibitor is selected from the group consisting of compounds P16, P17, P25, P44, P45, P62, P110, P121 , P137, P140, P151 , P156, P164, P174, P179, P182, P183, P188, P195, P196, P197, P210, P189, P232, P238, P240, 243, P249, P252, 255, P260, P262, P272, P273, P274, P276, P277, P280, P308, P328, P334, P340, P343, P347, P348, P349, P350, P351 , P352, P353, P354, P355, P356, P357, P358, P359, P360, P361 , P362, P363, and P364. E77. The method of claim E71 , wherein the Plk4 inhibitor is centrinone, CFI400945, or a pharmaceutically acceptable salt thereof.

[0468] E78. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the Haspin inhibitor.

[0469] E79. The method of claim E78, wherein the Haspin inhibitor is SEL120 or a pharmaceutically acceptable salt thereof.

[0470] E80. The method of any one of claims E1 to E19, wherein the method comprises the step of administering the Mettl3 inhibitor.

[0471] E81 . The method of claim E80, wherein the Mettl3 inhibitor is UZH1 a, sTC-15, or a pharmaceutically acceptable salt thereof.

[0472] E82. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the nucleoside analog.

[0473] E83. The method of claim E82, wherein the nucleoside analog is cytarabine, gemcitabine, mercaptopurine, azacytidine, cladribine, decitabine, fluorouracil, floxuridine, fludarabine, nelarabine, or a pharmaceutically acceptable salt thereof or a combination thereof.

[0474] E84. The method of claim E82 or claim E83, wherein the nucleoside analog is gemcitabine or a pharmaceutically acceptable salt thereof.

[0475] E85. The method of claim E82 or claim E83, wherein the nucleoside analog is fluorouracil or a pharmaceutically acceptable salt thereof.

[0476] E86. The method of claim E82 or claim E83, wherein the nucleoside analog is a combination of gemcitabine or a pharmaceutically acceptable salt thereof and fluorouracil or a pharmaceutically acceptable salt thereof.

[0477] E87. The method of any one of claims E1 to E16, wherein the method comprises the step of administering the platinum-based DNA damaging agent.

[0478] E88. The method of claim E87, wherein the platinum-based DNA damaging agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin.

[0479] E89. The method of claim E87, wherein the platinum-based DNA damaging agent is carboplatin.

[0480] E90. The method of any one of claims E16 to E89, wherein the Wee1 inhibitor, Fen1 inhibitor, Topi inhibitor, Rrm1 inhibitor, Rrm2 inhibitor, Aurkb inhibitor, Top2A inhibitor, Atr inhibitor, Ttk inhibitor, Sod1 inhibitor, Sod2 inhibitor, Bub1 inhibitor, Cdc7 inhibitor, Sae1 inhibitor, Plk1 inhibitor, Uba2 inhibitor, Dut inhibitor, Hdac3 inhibitor, Chekl inhibitor, Aurka inhibitor, Men1 inhibitor, Doti I inhibitor, Crebbp inhibitor, Ezh2 inhibitor, Plk4 inhibitor, Haspin inhibitor, Mettl3 inhibitor, nucleoside analog, platinum-based DNA damaging agent, or the combination thereof is administered as a pharmaceutical composition.

[0481] E91 . The method of any one of claims E1 to E90, wherein the Myt1 inhibitor is a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR2; R1and each R2are independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C2-9heterocyclyl, optionally substituted C2-9heterocyclyl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, cyano, –N(R7)2, –OR7, –C(O)N(R8)2, – SO2N(R8)2, –SO2R7A, or –Q–R7B; or R1combines with one R2that is vicinal to R1to form an optionally substituted C3-6alkylene; each of R3and R4is independently optionally substituted C1-6alkyl or halogen; R5is H or –N(R7)2; R6is –C(O)NH(R8), –C(O)R7A, or –SO2R7A; each R7is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or –SO2R7A; or two R7groups, together with the atom to which both are attached, combine to form an optionally substituted C2-9heterocyclyl; each R7Ais independently optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, or optionally substituted C6-10 aryl; each R7Bis independently hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, –N(R7)2, – C(O)N(R8)2, –SO2N(R8)2, –SO2R7A, or optionally substituted alkoxy; each R8is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8cycloalkyl, or optionally substituted C1-9heteroaryl; or two R8, together with the atom to which they are attached, combine to form an optionally substituted C2-9heterocyclyl; and Q is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, optionally substituted C3-8 cycloalkenylene optionally substituted C6-10arylene, optionally substituted C2-9heterocyclylene, or optionally substituted C1-9heteroarylene. E92. The method of claim E91, wherein the compound is enriched for the atropisomer of formula (IA):

[0482] (IA), or a pharmaceutically acceptable salt thereof.

[0483] E93. The method of claim E91 or E92, wherein X is CR2. E94. The method of claim E92, wherein the compound is of formula (II):

[0484] (ii); or a pharmaceutically acceptable salt thereof.

[0485] E95. The method of claim E94, wherein the compound is enriched for the atropisomer of formula (HA):

[0486] (HA); or a pharmaceutically acceptable salt thereof.

[0487] E96. The method of claim E91 , wherein the compound is of formula (III):

[0488] (HI); wherein R2Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted Ce-w aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, -N(R7)2, -OR7, -C(O)N(R8)2, -SO2N(R8)2, -SO2R7A, or -Q-R7B; or a pharmaceutically acceptable salt thereof.

[0489] E97. The method of claim E96, wherein the compound is enriched for the atropisomer of formula (IIIA):

[0490] (I HA); or a pharmaceutically acceptable salt thereof.

[0491] E98. The method of claim E96 or E97, wherein R2Ais hydrogen, optionally substituted C1-6 alkyl, or halogen.

[0492] E99. The method of any one of claims E91 to E98, wherein R3is optionally substituted C1-6 alkyl.

[0493] E100. The method of any one of claims E91 to E98, wherein R3is halogen.

[0494] E101 . The method of claim E100, wherein the halogen is chlorine.

[0495] E102. The method of any one of claims E91 to E101 , wherein R4is optionally substituted C1- e alkyl.

[0496] E103. The method of any one of claims E91 to E101 , wherein R4is halogen.

[0497] E104. The method of claim E103, wherein the halogen is chlorine.

[0498] E105. The method of any one of claims E91 to E104, wherein R2is hydrogen.

[0499] E106. The method of any one of claims E91 to E104, wherein R2is optionally substituted C1- e alkyl.

[0500] E107. The method of claim E106, wherein R2is optionally substituted methyl or optionally substituted isopropyl.

[0501] E108. The method of any one of claims E91 to E104, wherein R2is halogen.

[0502] E109. The method of any one of claims E91 to E108, wherein R1is hydrogen.

[0503] E110. The method of any one of claims E91 to E108, wherein R1is halogen.

[0504] E111 . The method of claim E110, wherein R1is chlorine or bromine.

[0505] E112. The method of any one of claims E91 to E108, wherein R1is optionally substituted C1- e alkyl.

[0506] E113. The method of claim E112, wherein R1is optionally substituted methyl, optionally substituted ethyl, optionally substituted isopropyl, or optionally substituted butyl.

[0507] E114. The method of any one of claims E91 to E108, wherein R1is optionally substituted C1- 9 heteroaryl.

[0508] E115. The method of claim E114, wherein R1is 1 ,3-thiazolyl, 1 ,2-thiazolyl, 1 ,3-oxazolyl, benzo-1 ,3-thiazolyl, benzo-1 ,3-oxazolyl, indolyl, benzimidazolyl, pyridyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, or pyrazolyl, wherein R1is optionally substituted with substituents as defined for optionally substituted C1-9 heteroaryl.

[0509] E116. The method of any one of claims E91 to E108, wherein R1is optionally substituted C3- s cycloalkyl.

[0510] E117. The method of claim E116, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R1is optionally substituted with substituents as defined for optionally substituted C3-8 cycloalkyl.

[0511] E118. The method of any one of claims E91 to E108, wherein R1is optionally substituted C2-

[0512] 9 heterocyclyl.

[0513] E119. The method of claim E118, wherein R1is 1 ,2,3,6-tetrahydropyridinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, oxa-aza-spiro[3,3]heptane, or oxa-aza-bicyclo[3.2.1]octane, wherein R1is optionally substituted with substituents as defined for optionally substituted C2-9 heterocyclyl.

[0514] E120. The method of any one of claims E91 to E108, wherein R1is optionally substituted C3- s cycloalkyl.

[0515] E121. The method of claim E120, wherein R1is optionally substituted cyclohexenyl or optionally substituted cyclopentenyl.

[0516] E122. The method of any one of claims E91 to E108, wherein R1is optionally substituted CB-

[0517] 10 aryl.

[0518] E123. The method of claim E122, wherein R1is optionally substituted phenyl.

[0519] E124. The method of any one of claims E91 to E108, wherein R1is -Q-R7B.

[0520] E125. The method of claim E124, wherein Q is optionally substituted C2-6 alkynylene.

[0521] E126. The method of claim E124, wherein Q is optionally substituted C1-6 alkylene.

[0522] E127. The method of claim E124, wherein Q is optionally substituted Cs-w arylene.

[0523] E128. The method of any one of claims E124 to E127, wherein R7Bis optionally substituted C2-9 heterocyclyl.

[0524] E129. The method of any one of claims E124 to E127, wherein R7Bis optionally substituted CB-IO aryl.

[0525] E130. The method of any one of claims E91 to E129, wherein R1is optionally substituted with one, two, or three groups independently selected from the group consisting of methyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, -C(O)NH2, - C(O)NH(Me), -C(O)N(Me)2, -(CH2)n-C(O)OH, and -(CH2)n-C(O)Ot-Bu, wherein n is 0 or 1.

[0526] E131 . The method of any one of claims E91 to E108, wherein R1is -N(R7)2.

[0527] E132. The method of claim E131 , wherein R1is diethylamino.

[0528] E133. The method of any one of claims E91 to E132, wherein R5is hydrogen.

[0529] E134. The method of any one of claims E91 to E132, wherein R5is -N(R7)2.

[0530] E135. The method of claim E134, wherein R5is -NH2.

[0531] E136. The method of any one of claims E91 to E135, wherein R6is -C(O)NH(R8).

[0532] E137. The method of any one of claims E91 to E136, wherein R6is -C(O)NH2.

[0533] E138. The method of any one of claims E91 to E136, wherein R6is -C(O)NH(Me). E139. The method of any one of claims E91 to E135, wherein R6is -SC>2R7A.

[0534] EMO. The method of claim E139, wherein R6is - SC>2Me.

[0535] E141. The method of any one of claims E1 to E90, wherein the Myt1 inhibitor is selected from the group consisting of compounds 1-328 and pharmaceutically acceptable salts thereof. E142. The method of any one of claims E1 to E141 , wherein the Myt1 inhibitor is administered as a pharmaceutical composition.

[0536] OTHER EMBODIMENTS

[0537] Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.

[0538] Other embodiments are in the claims.

Claims

CLAIMS1 . A method for treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a membrane-associated tyrosine and threonine-specific cdc2-inhibatory kinase (Myt1) inhibitor, wherein the cancer comprises a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAE, or a prior or current infection with HPV.

2. A method for treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a membrane-associated tyrosine and threonine-specific cdc2-inhibatory kinase (Myt1) inhibitor, wherein the cancer comprises a cancer previously identified as a cancer comprising a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

3. A method of inducing death in a cancer cell, the method comprising contacting the cell with an effective amount of a Myt1 inhibitor, wherein the cancer comprises a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

4. A method of inducing death in a cancer cell, the method comprising contacting the cell with an effective amount of a Myt1 inhibitor, wherein the cancer comprises a cancer previously identified as a cancer comprising a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV.

5. The method of any one of claims 1 to 4, wherein the cancer comprises a KRAS mutation.

6. The method of claim 5, wherein the KRAS mutation encodes for an amino acid substitution in a Kras protein, wherein the amino acid substitution is G12D, G12V, G12C, G13D, G12R, G12A, Q61 H, G12S, A146T, G13C, Q61 L, Q61 R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, or combinations thereof.

7. The method of claim 5 or claim 6, wherein the cancer comprises colorectal cancer, pancreatic cancer, lung cancer, uterine cancers, ovarian cancer, cervical cancer or gastro-esophageal cancer.

8. The method of any one of claims 1 to 4, wherein the cancer comprises KRAS amplification.

9. The method of any one of claims 1 to 4, wherein the cancer comprises an HRAS mutation.

10. The method of claim 9, wherein the HRAS mutation encodes for an amino acid substitution in an HRAS protein, wherein the amino acid substitution is Q61 R, G13R, Q61 K, G12S, Q61 L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61 H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, or combinations thereof.11 . The method of claim 9 or claim 10, wherein the cancer comprises kidney cancer, bladder cancer, head and neck cancer, or thyroid cancer.

12. The method of any one of claims 1 to 4, wherein the cancer comprises an NRAS mutation.

13. The method of claim 12, wherein the NRAS mutation encodes for an amino acid substitution in an NRAS protein, wherein the amino acid substitution is Q61 R, Q61 K, G12D, Q61 L, Q61 H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61 P, A59D, E132K, E49K, T50I, A146V, orA59T, or combinations thereof.

14. The method of claim 12 or claim 13, wherein the cancer comprises colorectal cancer, thyroid cancer, or melanoma.

15. The method of any one of claims 5 to 14, wherein the cancer further comprises a TP53 mutation.

16. The method of any one of claims 1 to 4, wherein the cancer is uterine cancer, ovarian cancer, cervical cancer, bladder cancer, brain cancer, pancreatic cancer, mesothelioma, kidney cancer, gastric cancer, colorectal cancer, head and neck cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, thyroid cancer, melanoma, or endometrial cancer.

17. The method of any one of claims 1 to 16, wherein the Myt1 inhibitor is a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR2; R1and each R2are independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C2-9heterocyclyl, optionally substituted C2-9heterocyclyl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, cyano, –N(R7)2, –OR7, –C(O)N(R8)2, – SO2N(R8)2, –SO2R7A, or –Q–R7B; or R1combines with one R2that is vicinal to R1to form an optionally substituted C3-6alkylene; each of R3and R4is independently optionally substituted C1-6alkyl or halogen; R5is H or –N(R7)2; R6is –C(O)NH(R8), –C(O)R7A, or –SO2R7A; each R7is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or –SO2R7A; or two R7groups, together with the atom to which both are attached, combine to form an optionally substituted C2-9heterocyclyl; each R7Ais independently optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, or optionally substituted C6-10 aryl; each R7Bis independently hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, –N(R7)2, – C(O)N(R8)2, –SO2N(R8)2, –SO2R7A, or optionally substituted alkoxy; each R8is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8cycloalkyl, or optionally substituted C1-9heteroaryl; or two R8, together with the atom to which they are attached, combine to form an optionally substituted C2-9heterocyclyl; and Q is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene, optionally substituted C2-6 alkynylene, optionally substituted C3-8 cycloalkylene, optionally substituted C3-8 cycloalkenylene optionally substituted C6-10arylene, optionally substituted C2-9heterocyclylene, or optionally substituted C1-9heteroarylene;wherein the C2-9 heterocyclyl, C2-9 heterocyclyl C1-6 alkyl, C1-9 heteroaryl, and C1-9 heteroaryl C1-6alkyl groups each contain one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

18. The method of claim 17, wherein the compound is enriched for the atropisomer of formula (IA):or a pharmaceutically acceptable salt thereof.

19. The method of claim 17 or 18, wherein X is CR2.

20. The method of claim 17, wherein the compound is of formula (II):or a pharmaceutically acceptable salt thereof.

21. The method of claim 20, wherein the compound is enriched for the atropisomer of formula (IIA):or a pharmaceutically acceptable salt thereof.

22. The method of claim 17, wherein the compound is of formula (III):(III); wherein R2Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C2-9heterocyclyl, optionally substituted C2-9heterocyclyl C1-6alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, –N(R7)2, –OR7, –C(O)N(R8)2, –SO2N(R8)2, –SO2R7A, or –Q–R7B; or a pharmaceutically acceptable salt thereof.

23. The method of claim 22, wherein the compound is enriched for the atropisomer of formula (IIIA):or a pharmaceutically acceptable salt thereof.

24. The method of claim 22 or 23, wherein R2Ais hydrogen, optionally substituted C1-6alkyl, or halogen.

25. The method of any one of claims 17 to 24, wherein R3is optionally substituted C1-6alkyl.

26. The method of any one of claims 17 to 24, wherein R3is halogen.

27. The method of claim 26, wherein the halogen is chlorine.

28. The method of any one of claims 17 to 27, wherein R4is optionally substituted C1-6 alkyl.

29. The method of any one of claims 17 to 27, wherein R4is halogen.

30. The method of claim 29, wherein the halogen is chlorine.

31. The method of any one of claims 17 to 30, wherein R2is hydrogen.

32. The method of any one of claims 17 to 31, wherein R2is optionally substituted C1-6 alkyl.

33. The method of claim 32, wherein R2is optionally substituted methyl or optionally substituted isopropyl.

34. The method of any one of claims 17 to 30, wherein R2is halogen.

35. The method of any one of claims 17 to 34, wherein R1is hydrogen.

36. The method of any one of claims 17 to 34, wherein R1is halogen.

37. The method of claim 36, wherein R1is chlorine or bromine.

38. The method of any one of claims 17 to 34, wherein R1is optionally substituted C1-6alkyl.

39. The method of claim 38, wherein R1is optionally substituted methyl, optionally substituted ethyl, optionally substituted isopropyl, or optionally substituted butyl.

40. The method of any one of claims 17 to 34, wherein R1is optionally substituted C1-9 heteroaryl.

41. The method of claim 40, wherein R1is 1,3-thiazolyl, 1,2-thiazolyl, 1,3-oxazolyl, benzo- 1,3-thiazolyl, benzo-1,3-oxazolyl, indolyl, benzimidazolyl, pyridyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, or pyrazolyl, wherein R1is optionally substituted with substituents as defined for optionally substituted C1-9heteroaryl.

42. The method of any one of claims 17 to 34, wherein R1is optionally substituted C3-8 cycloalkyl.

43. The method of claim 42, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein R1is optionally substituted with substituents as defined for optionally substituted C3-8cycloalkyl.

44. The method of any one of claims 17 to 34, wherein R1is optionally substituted C2-9 heterocyclyl.

45. The method of claim 44, wherein R1is 1,2,3,6-tetrahydropyridinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, oxa-aza-spiro[3,3]heptane, or oxa-aza-bicyclo[3.2.1]octane, wherein R1is optionally substituted with substituents as defined for optionally substituted C2-9heterocyclyl.

46. The method of any one of claims 17 to 34, wherein R1is optionally substituted C3-8 cycloalkyl.

47. The method of claim 46, wherein R1is optionally substituted cyclohexenyl or optionally substituted cyclopentenyl.

48. The method of any one of claims 17 to 34, wherein R1is optionally substituted C6-10aryl.

49. The method of claim 48, wherein R1is optionally substituted phenyl.

50. The method of any one of claims 17 to 34, wherein R1is –Q–R7B.

51. The method of claim 50, wherein Q is optionally substituted C2-6alkynylene.

52. The method of claim 50, wherein Q is optionally substituted C1-6 alkylene.

53. The method of claim 50, wherein Q is optionally substituted C6-10arylene.

54. The method of any one of claims 50 to 53, wherein R7Bis optionally substituted C2-9 heterocyclyl.

55. The method of any one of claims 50 to 53, wherein R7Bis optionally substituted C6-10aryl.

56. The method of any one of claims 17 to 55, wherein R1is optionally substituted with one, two, or three groups independently selected from the group consisting of methyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, -C(O)NH2, -C(O)NH(Me), - C(O)N(Me)2, -(CH2)n-C(O)OH, and -(CH2)n-C(O)Ot-Bu, wherein n is 0 or 1.

57. The method of any one of claims 17 to 34, wherein R1is –N(R7)2.

58. The method of claim 57, wherein R1is diethylamino.

59. The method of any one of claims 17 to 58, wherein R5is hydrogen.

60. The method of any one of claims 17 to 58, wherein R5is –N(R7)2.

61. The method of claim 60, wherein R5is –NH2.

62. The method of any one of claims 17 to 61, wherein R6is –C(O)NH(R8).

63. The method of any one of claims 17 to 62, wherein R6is –C(O)NH2.

64. The method of any one of claims 17 to 62, wherein R6is –C(O)NH(Me).

65. The method of any one of claims 17 to 61, wherein R6is –SO2R7A.

66. The method of claim 65, wherein R6is –SO2Me.

67. The method of any one of claims 1 to 16, wherein the Myt1 inhibitor is selected from the group consisting of compounds 1-328 and pharmaceutically acceptable salts thereof.

68. The method of any one of claims 1 to 67, wherein the Myt1 inhibitor is administered as a pharmaceutical composition.

69. The method of any one of claims 1 to 68, further comprises administration of a therapeutically effective amount of a Wee1 inhibitor, Fen1 inhibitor, Top1 inhibitor, Rrm1 inhibitor, Rrm2 inhibitor, Aurkb inhibitor, Top2A inhibitor, Atr inhibitor, Ttk inhibitor, Sod1 inhibitor, Sod2 inhibitor, Bub1 inhibitor, Cdc7 inhibitor, Sae1 inhibitor, Plk1 inhibitor, Uba2 inhibitor, Dut inhibitor, Hdac3 inhibitor, Chek1 inhibitor, Aurka inhibitor, Men1 inhibitor, Dot1l inhibitor, Crebbp inhibitor, Ezh2 inhibitor, Plk4 inhibitor, Haspin inhibitor, Mettl3 inhibitor, nucleoside analog, platinum-based DNA damaging agent, or a combination thereof.

70. The method of any one of claims 1 to 69, wherein the method comprises administering the Wee1 inhibitor.

71. The method of claim 70, wherein the Wee1 inhibitor is one of:

72. The method of any one of claims 1 to 68, wherein the method comprises administering the Fen1 inhibitor.

73. The method of claim 72, wherein the Fen1 inhibitorpharmaceutically acceptable salt thereof.

74. The method of any one of claims 1 to 68, wherein the method comprises administering the Topi inhibitor.

75. The method of claim 74, wherein the Topi inhibitor is irinotecan, topotecan, camptothecin, lamellarin D, or a pharmaceutically acceptable salt thereof.

76. The method of any one of claims 1 to 68, wherein the method comprises administering the Rrm1 inhibitor.

77. The method of any one of claims 1 to 76, wherein the method comprises administering the Rrm2 inhibitor.

78. The method of claim 77, wherein the Rrm2 inhibitor is motexafin gadolinium, hydroxyurea, fludarabine, cladribine, tezacitabine, triapine, or a pharmaceutically acceptable salt thereof.

79. The method of any one of claims 1 to 68, wherein the method comprises administering the Aurkb inhibitor.

80. The method of claim 79, wherein the Aurkb inhibitor is MK-0457, AZD1152, PHA739358, AT9283, AMG900, SNS-314, TAK-901 , CYC116, GSK1070916, PF03814735, or a pharmaceutically acceptable salt thereof.81 . The method of any one of claims 1 to 68, wherein the method comprises administering the Top2A inhibitor.

82. The method of claim 81 , wherein the Top2A inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, or a pharmaceutically acceptable salt thereof.

83. The method of any one of claims 1 to 68, wherein the method comprises administering the Atr inhibitor.

84. A method for treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of (i) a Myt1 inhibitor, or a pharmaceutically acceptable salt, and (i) a Atr inhibitor, or a pharmaceutically acceptable salt, wherein the cancer comprises a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV, each in an amount that together is effective to treat the cancer.

85. A method for treating a cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of (i) a Myt1 inhibitor, or a pharmaceutically acceptable salt, and (ii) a Atr inhibitor, or a pharmaceutically acceptable salt, wherein the cancer comprises a cancer previously identified as a cancer comprising a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV, each in an amount that together is effective to treat the cancer.

86. A method of inducing death in a cancer cell, the method comprising administering to a subject in need thereof a thereof, the method comprising contacting the cell with an effective amounteffective amount of (ii) an Atr inhibitor, or a pharmaceutically acceptable salt, wherein the cancer comprises a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV, each in an amount that together is effective to treat the cancer.

87. A method of inducing death in a cancer cell, the method comprising contacting the cell with an effective amount of (i) a Myt1 inhibitor, or a pharmaceutically acceptable salt, and an effective amount of (ii) an Atr inhibitor, or a pharmaceutically acceptable salt, wherein the cancer comprises a cancer previously identified as a cancer comprising a mutation in, an amplification of, or the overexpression of KRAS, NRAS, HRAS, TP53, CDK4, CDK6, CDK12, CDKN2A, CDC25A, EGFR, c-MYC, PIK3CA, PPP2R1A, PTEN, RB1, BRAF, or a prior or current infection with HPV, each in an amount that together is effective to treat the cancer.

88. The method of any one of claims 83 to 87, wherein the Atr inhibitor is a compound of formula (IV):or a pharmaceutically acceptable salt thereof, wherein is a double bond, and each W is independently N or CR12; or is a single bond, and each W is independently NRW, carbonyl, or C(RW)2; wherein each RWis independently H or optionally substituted C1-6 alkyl; R9is optionally substituted C1-6 alkyl or H; R10is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocyclyl C1-6 alkyl, optionally substituted C6- 10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, halogen, –N(R13)2, –OR13, –CON(R14)2, –SO2N(R14)2,–SO2R13A, or –U–R13B; R11is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R12is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; each R13is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6- 10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or –SO2R13A; or both R13, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl;both R13, together with the atom to which they are attached, combine to form an optionally substituted C2-9heterocyclyl; each R13Ais independently optionally substituted C1-6alkyl, optionally substituted C3-8cycloalkyl, or optionally substituted C6-10 aryl; R13Bis hydroxyl, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9heteroaryl, –N(R13)2, –CON(R14)2, –SO2N(R14)2, –SO2R13A, or optionally substituted alkoxy; each R14is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2- 6 alkoxyalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C3-8cycloalkyl, or optionally substituted C1-9heteroaryl; or both R14, together with the atom to which they are attached, combine to form an optionally substituted C2-9heterocyclyl; U is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; and V is hydrogen or halogen; wherein the C2-9heterocyclyl, C2-9heterocyclyl C1-6alkyl, C1-9heteroaryl, and C1-9heteroaryl C1-6 alkyl groups each contain one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

89. The method of any one of claims 83 to 87, wherein the Atr inhibitor is a compound of formula (V):or a pharmaceutically acceptable salt thereof, wherein each W is independently N or CR12; R9is optionally substituted C1-6 alkyl or H; R10is optionally substituted C2-9 heterocyclyl, optionally substituted C1-6 alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C2-9heterocyclyl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, halogen, –N(R13)2, –OR13, –CON(R14)2, –SO2N(R14)2,–SO2R13A, or –U–R13B; R11is optionally substituted C1-9 heteroaryl or optionally substituted C1-9 heteroaryl C1-6 alkyl; each R12is independently hydrogen, halogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl;each R13is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9heteroaryl, or –SO2R13A; or both R13, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; each R13Ais independently optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C6-10aryl; R13Bis hydroxyl, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C1-9 heteroaryl, –N(R13)2, –CON(R14)2, –SO2N(R14)2, –SO2R13A, or optionally substituted alkoxy; each R14is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkoxyalkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heteroaryl; or both R14, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl; U is optionally substituted C2-9heterocyclylene, optionally substituted C3-8cycloalkylene, optionally substituted C1-9heteroarylene, or optionally substituted C6-10arylene; and V is hydrogen or halogen; wherein the C2-9 heterocyclyl, C2-9 heterocyclyl C1-6 alkyl, C1-9 heteroaryl, and C1-9 heteroaryl C1-6alkyl groups each contain one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

90. The method of any one of claims 83 to 89, wherein the Atr inhibitor is selected from the group consisting of compounds A43, A57, A62, A87, A93, A94, A95, A99, A100, A106, A107, A108, A109, A111, A112, A113, A114, A115, A116, A118, A119, A120, A121 (camonsertib), A122, A123, A135, A147, A148, and pharmaceutically acceptable salts thereof.

91. The method of any one of claims 83 to 90, wherein the Atr inhibitor is compound A43 or a pharmaceutically acceptable salt thereof.

92. The method of any one of claims83 to 90, wherein the Atr inhibitor is camonsertib or a pharmaceutically acceptable salt thereof.

93. The method of any one of claims 83 to 90, wherein the Atr inhibitor is compound A122 or a pharmaceutically acceptable salt thereof.

94. The method of any one of claims 83 to 87, wherein the Atr inhibitor iselimusertib (BAY1895344) ceralasertib (AZD6738) berzosertib (VE-822)SKLB-197 or a pharmaceutically acceptable salt thereof.

95. The method of any one of claims 1 to 16, wherein the method comprises administering the Ttk inhibitor.

96. The method of claim 95, wherein the Ttk inhibitor is BAY1217389 or a pharmaceutically acceptable salt thereof.

97. The method of any one of claims 1 to 16, wherein the method comprises administering the Sod1 inhibitor.

98. The method of claim 97, wherein the Sod1 inhibitor is LCS1 , ATN-224,Pyrimethamine, a compound of the structure:or a pharmaceutically acceptable salt thereof.

99. The method of any one of claims 1 to 16, wherein the method comprises administering the Sod2 inhibitor.

100. The method of claim 99, wherein the Sod2 inhibitor is LCS1 , ATN-224, pyrimethamine, or a pharmaceutically acceptable salt thereof.

101. The method of any one of claims 1 to 16, wherein the method comprises administering the Bub1 inhibitor.

102. The method of claim 101 , wherein the Bub1 inhibitor is BAY-320, BAY-419, BAY1816032, or a pharmaceutically acceptable salt thereof.

103. The method of any one of claims 1 to 16, wherein the method comprises administering the Cdc7 inhibitor.

104. The method of claim 103, wherein the Cdc7 inhibitor is SRA141 , TAK931 , or a pharmaceutically acceptable salt thereof.

105. The method of any one of claims 1 to 16, wherein the method comprises administering the Sae1 inhibitor.

106. The method of claim 105, wherein the Sae1 inhibitor is ML792 or a pharmaceutically acceptable salt thereof.

107. The method of any one of claims 1 to 16, wherein the method comprises administering the Plk1 inhibitor.

108. The method of claim 107, wherein the Plk1 inhibitor is BI2536, BI6727, TAK960, NMSP937, GSK461364, or a pharmaceutically acceptable salt thereof.

109. The method of any one of claims 1 to 16, wherein the method comprises administering the Uba2 inhibitor.

110. The method of claim 109, wherein the Uba2 inhibitor is TAK981 or a pharmaceutically acceptable salt thereof.

111. The method of any one of claims 1 to 16, wherein the method comprises administering the Dut inhibitor.

112. The method of claim 111 , wherein the Dut inhibitor is TAS114 or a pharmaceutically acceptable salt thereof.

113. The method of any one of claims 1 to 16, wherein the method comprises administering the Hdac3 inhibitor.

114. The method of claim 113, wherein the Hdac3 inhibitor is RGFP966 or a pharmaceutically acceptable salt thereof.

115. The method of any one of claims 1 to 16, wherein the method comprises administering the Chekl inhibitor.

116. The method of claim 115, wherein the Chekl inhibitor is SRA737 or a pharmaceutically acceptable salt thereof.

117. The method of any one of claims 1 to 16, wherein the method comprises administering the Aurka inhibitor.

118. The method of claim 117, wherein the Aurka inhibitor is MLN8237, MK-0457, MLN8054, PHA739358, AT9283, AMG900, MK5108, SNS314, TAK901 , CYC116, ENMD2076, or a pharmaceutically acceptable salt thereof.

119. The method of any one of claims 1 to 16, wherein the method comprises administering the Men1 inhibitor.

120. The method of claim 119, wherein the Men1 inhibitor is MI3454, SNDX5613, VTP50469, KO539, or a pharmaceutically acceptable salt thereof.

121. The method of any one of claims 1 to 16, wherein the method comprises administering the Doti I inhibitor.

122. The method of claim 121 , wherein the Doti I inhibitor is EPZ5676 or a pharmaceutically acceptable salt thereof.

123. The method of any one of claims 1 to 16, wherein the method comprises administering the Crebbp inhibitor.

124. The method of claim 123, wherein the Crebbp inhibitor is CPI4, CCS1477, E7386, NEO1132, NEO2734, PRI724, C82, BC001 , C646, EML425, CBP30, or a pharmaceutically acceptable salt thereof.

125. The method of any one of claims 1 to 16, wherein the method comprises administering the Ezh2 inhibitor.

126. The method of claim 125, wherein the Ezh2 inhibitor is EPZ-6438, GSK126, or a pharmaceutically acceptable salt thereof.

127. The method of any one of claims 1 to 16, wherein the method comprises administering the Plk4 inhibitor.

128. The method of claim 127, wherein the Plk4 inhibitor is a compound of formula (VI)or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 , 2, 3, or 4; m is 0, 1 , or 2;L is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted Ce-w aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of RL;R15Ais hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or nitrile;R15Bis hydrogen; orR15Aand R15B, together with the atoms to which they are attached, are C2-9 heterocyclyl, Ce-w aryl, or C1-9 heteroaryl;A is O or S, and RA’ and RA" are both absent; or A is N, RAis absent, and RA" is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Ce-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl, or RA" and L, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl or optionally substituted C2-9 heteroaryl; or A is C, and each of RAand RA" are independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; each RLis independently halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ce-w aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, -S(O)mRLA, -N(RLB)2, or - ORLB;RLAis optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -ORLBor -N(RLB)2 each RLBis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted CB- 10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; or two RLBgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl;J is N, and R4is absent; or J is C, and R4is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;R17is optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -CONH2, or -E-R17A;E is optionally substituted amino, optionally substituted C2-9 heterocyclylene, optionally substituted C2-9 heteroarylene, optionally substituted Ce-w arylene, or optionally substituted C3-8 cycloalkylene;R17Ais hydrogen, halogen, cyano, optionally substituted C1-6 alkylsulfonyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted Cs-w aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9 heteroaryl;R18is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or -OR18A; andR18Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, or optionally substituted C3-8 cycloalkyl; wherein the C1-6 heteroalkyl, C2-9 heterocyclyl, C2-9 heterocyclyl C1-6 alkyl, C1-9 heteroaryl, and C1-9 heteroaryl C1-6 alkyl groups each contain one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

129. The method of claim 127 or claim 128, wherein the Plk4 inhibitor is a compound of formula (VII)(VII), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 , 2, 3, or 4; m is 0, 1 , or 2;L is optionally substituted C2-9 heterocyclyl, optionally substituted C2-9 heteroaryl, optionally substituted Cs-w aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of RL;R15Ais hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or nitrile;R15Bis hydrogen; orR15Aand R15B, together with the atoms to which they are attached, are C2-9 heterocyclyl, Cs-w aryl, or C1-9 heteroaryl;A is O or S, and RA’and RA”are both absent; or A is N, RA’is absent, and RA”is hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl, or RA”and L, together with the atom to which they are attached, combine to form an optionally substituted C2-9heterocyclyl or optionally substituted C2-9heteroaryl; or A is C, and each of RA’and RA”are independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, or optionally substituted C1-6alkylsulfonyl; each RLis independently halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, -S(O)mRLA, -N(RLB)2, or - ORLB; RLAis optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, -ORLBor -N(RLB)2. each RLBis independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; or two RLBgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9heterocyclyl; R17is optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9heteroaryl, -CONH2, or -E-R17A; E is optionally substituted amino, optionally substituted C2-9heterocyclylene, optionally substituted C2-9 heteroarylene, optionally substituted C6-10 arylene, or optionally substituted C3-8 cycloalkylene; R17Ais hydrogen, halogen, cyano, optionally substituted C1-6alkylsulfonyl, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9heteroaryl; R18is hydrogen, halogen, cyano, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or -OR18A; andR18Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, or optionally substituted C3-8cycloalkyl; wherein the C1-6heteroalkyl, C2-9heterocyclyl, C2-9heterocyclyl C1-6alkyl, C1-9heteroaryl, and C1-9 heteroaryl C1-6 alkyl groups each contain one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

130. The method of claim 127 or claim 128, wherein the Plk4 inhibitor is a compound of formula (VIII)(VIII), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; L is optionally substituted C2-9heterocyclyl, optionally substituted C2-9heteroaryl, optionally substituted C6-10 aryl, or optionally substituted C3-8 cycloalkyl, wherein L is further optionally substituted by n occurrences of RL; R15Ais hydrogen, halogen, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8 cycloalkyl, or nitrile; R15Bis hydrogen; or R15Aand R15B, together with the atoms to which they are attached, are C2-9heterocyclyl, C6-10aryl, or C1-9heteroaryl; A is O or S, and RA’and RA”are both absent; or A is N, RA’is absent, and RA”is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C6-10 aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, or optionally substituted C1-6 alkylsulfonyl, or RA”and L, together with the atom to which they are attached, combine to form an optionally substituted C2-9 heterocyclyl or optionally substituted C2-9 heteroaryl; or A is C, and each of RA’and RA”are independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl,optionally substituted C1-9 heteroaryl, optionally substituted C1-9 heteroaryl C1-6 alkyl, or optionally substituted C1-6alkylsulfonyl; each RLis independently halogen, cyano, optionally substituted C1-6alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8cycloalkenyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6alkyl, -S(O)mRLA, -N(RLB)2, or - ORLB; RLAis optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, -ORLBor -N(RLB)2. each RLBis independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10aryl C1-6alkyl, optionally substituted C3-8cycloalkyl, optionally substituted C6-10aryl, optionally substituted C2-9heterocyclyl, optionally substituted C1-9heteroaryl, optionally substituted C1-9heteroaryl C1-6 alkyl, or optionally substituted C1-6 alkylsulfonyl; or two RLBgroups, together with the atom to which both are attached, combine to form an optionally substituted C2-9 heterocyclyl; R16is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9heteroaryl; R17is optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, optionally substituted C1-9heteroaryl, -CONH2, or -E-R17A; E is optionally substituted amino, optionally substituted C2-9heterocyclylene, optionally substituted C2-9 heteroarylene, optionally substituted C6-10 arylene, or optionally substituted C3-8 cycloalkylene; R17Ais hydrogen, halogen, cyano, optionally substituted C1-6alkylsulfonyl, optionally substituted C1-6alkyl, optionally substituted C1-6heteroalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C6-10 aryl, optionally substituted C2-9 heterocyclyl, or optionally substituted C1-9heteroaryl; R18is hydrogen, halogen, cyano, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or -OR18A; and R18Ais hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, or optionally substituted C3-8cycloalkyl;wherein the C1-6 heteroalkyl, C2-9 heterocyclyl, C2-9 heterocyclyl C1-6 alkyl, C1-9 heteroaryl, and C1-9heteroaryl C1-6alkyl groups each contain one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

131. The method of any one of claims 127 to 130, wherein the Plk4 inhibitor is selected from the group consisting of compound P1 to P328.

132. The method of claim 127 to 131, wherein the Plk4 inhibitor is selected from the group consisting of compounds P16, P17, P25, P44, P45, P62, P110, P121, P137, P140, P151, P156, P164, P174, P179, P182, P183, P188, P195, P196, P197, P210, P189, P232, P238, P240, 243, P249, P252, 255, P260, P262, P272, P273, P274, P276, P277, P280, P308, P328, P334, P340, P343, P347, P348, P349, P350, P351, P352, P353, P354, P355, P356, P357, P358, P359, P360, P361, P362, P363, and P364.

133. The method of claim 127, wherein the Plk4 inhibitor is centrinone, CFI400945, or a pharmaceutically acceptable salt thereof.

134. The method of any one of claims 1 to 16, wherein the method comprises administering the Haspin inhibitor.

135. The method of claim 134, wherein the Haspin inhibitor is SEL120 or a pharmaceutically acceptable salt thereof.

136. The method of any one of claims 1 to 16, wherein the method comprises administering the Mettl3 inhibitor.

137. The method of claim 136, wherein the Mettl3 inhibitor is UZH1a, sTC-15, or a pharmaceutically acceptable salt thereof.

138. The method of any one of claims 1 to 16, wherein the method comprises administering the nucleoside analog.

139. The method of claim 138, wherein the nucleoside analog is cytarabine, gemcitabine, mercaptopurine, azacytidine, cladribine, decitabine, fluorouracil, floxuridine, fludarabine, nelarabine, or a pharmaceutically acceptable salt thereof or a combination thereof.

140. The method of claim 138 or claim 139, wherein the nucleoside analog is gemcitabine or a pharmaceutically acceptable salt thereof.

141. The method of claim 138 or claim 139, wherein the nucleoside analog is fluorouracil or a pharmaceutically acceptable salt thereof.

142. The method of claim 138 or claim 139, wherein the nucleoside analog is a combination of gemcitabine or a pharmaceutically acceptable salt thereof and fluorouracil or a pharmaceutically acceptable salt thereof.

143. The method of any one of claims 1 to 16, wherein the method comprises administering the platinum-based DNA damaging agent.

144. The method of claim 143, wherein the platinum-based DNA damaging agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin.

145. The method of claim 143, wherein the platinum-based DNA damaging agent is carboplatin.

146. The method of any one of claims 16 to 145, wherein the Wee1 inhibitor, Fen1 inhibitor, Top1 inhibitor, Rrm1 inhibitor, Rrm2 inhibitor, Aurkb inhibitor, Top2A inhibitor, Atr inhibitor, Ttk inhibitor, Sod1 inhibitor, Sod2 inhibitor, Bub1 inhibitor, Cdc7 inhibitor, Sae1 inhibitor, Plk1 inhibitor, Uba2 inhibitor, Dut inhibitor, Hdac3 inhibitor, Chek1 inhibitor, Aurka inhibitor, Men1 inhibitor, Dot1l inhibitor, Crebbp inhibitor, Ezh2 inhibitor, Plk4 inhibitor, Haspin inhibitor, Mettl3 inhibitor, nucleoside analog, platinum-based DNA damaging agent, or the combination thereof is administered as a pharmaceutical composition.

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