Prostate-specific membrane antigen (PSMA)-targeted poly(ADP-ribose) polymerase (PARP) inhibitor and related composition and method of use

Abstract

Conjugates of the formula: T-L(Alb)-A in which: T is a ligand that targets prostate-specific membrane antigen (PSMA); A is an inhibitor of poly(ADP-ribose) polymerase (PARP), L is a linker, which links T and A; and Alb is an optional albumin-binding group, in which case L is linked to Alb; with the proviso that A is not Inhibitoren, Rucaparib, Olaparib, Niraparib, Veliparib, Iniparib, Pamiparib, EB-47, or Talazoparib; pharmaceutical compositions; and methods of use.

Description

PROSTATE-SPECIFIC MEMBRANE ANTIGEN (PSMA)-TARGETED POLY(ADP-RIBOSE) POLYMERASE (PARP) INHIBITORAND RELATED COMPOSITION AND METHOD OF USECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No.63 / 720,837, filed November 15, 2024, the entire contents of which are hereby incorporated by reference as if fully set forth herein.STATEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under W81XWH-21-1-0473 awarded by the Defense Health Agency, Medical Research and Development Branch. The government has certain rights in the invention.TECHNICAL FIELD

[0003] The present disclosure relates to the use of ligands, which bind to prostate-specific membrane antigen (PSMA), to deliver poly(ADP-ribose) polymerase (PARP) inhibitors to which they are conjugated. The present disclosure also relates to pharmaceutical compositions comprising the conjugates and methods of using the conjugates, or the pharmaceutical compositions comprising them, to treat PSMA-expressing cancer.BACKGROUND

[0004] Prostate-specific membrane antigen (PSMA) is over-expressed on the membrane of aggressive forms of prostate cancer, many other human cancers, and endothelial cells of tumor neovasculature. Other PSMA-expressing cancers include, but are not limited to, breast cancer, lung cancer, colorectal cancer, renal cell carcinoma, primary glioma, pancreatic ducal adenocarcinoma, thyroid cancer, hepatocellular cancer, and salivary gland tumor.

[0005] Radiopharmaceutical therapies (RPT) targeting advanced PSMA-expressing prostate cancer have been tested in many clinical trials with unprecedented success. RPTs using [B-particle emitters (e.g., Lu- 177) have shown great efficacy with minimal side effects, but a majority of treated patients relapse, requiring repeated treatments. Trials with a-particle emitters (e g. Ac-225) have shown enhanced efficacy, but also toxicity, including lethal renal failure, xerostomia, and alacrima. These toxi cities are due to the expression of PSMA in some normal tissues, and the inability for current RPT agents to distinguish PSMA-expressing cancer cells from normal cells. In addition, RPT tends to be used primarily in major medical centers with the capacity to work with the high levels of radioactivity required for such therapies.

[0006] There are currently several approved poly(ADP -ribose) polymerase (PARP) inhibitors (e.g., niraparib, olaparib, rucaparib and talazoparib), with many more currently in clinical trials. PARPs are a family of enzymes involved in DNA damage repair (DDR). PARP inhibition leads to accumulation of single-stranded breaks (SSBs), which then leads to an accumulation of double stranded breaks (DSBs). Cells with an increasing number of DSBs are more dependent on other DNA repair pathways, mainly the homologous recombination (HR) repair pathway. Cancer cells with HR deficiencies, such as ovarian, breast, and prostate cancers, therefore, even more susceptible to PARP impairment of the base excision repair (BER) pathway.

[0007] It is an object of the present disclosure to provide PSMA-targeted PARP inhibitors as a therapeutic for treating cancers characterized by both PSMA upregulation and HR deficiencies. It is another object of the present disclosure to increase the half-life of PSMA-targeted PARP inhibitors in blood. Further, there is a need for developing either new PSMA-targeted agents that are non-radioactive and that are capable of selectively targeting cancers or, at a minimum, PSMA-targeted agents that are radioactive but enable a reduction in the dose of radiation effective for treatment. These and other objects and advantages, as well as inventive features, will be apparent from the detailed description provided herein.SUMMARY

[0008] Provided are PSMA-targeted PARP inhibitors comprising conjugates of the formula T-L(Alb)-A in which: T is a ligand that targets prostate-specific membrane antigen (PSMA); A is an inhibitor of poly(ADP-ribose) polymerase (PARP), Lis a linker, which links T and A; and Alb is an optional albumin-binding group, in which case L is linked to Alb; with the proviso that A is not Inhibitoren, Rucaparib, Olaparib, Niraparib, Iniparib, Pamiparib, EB-47, or Talazoparib.

[0009] In embodiments, T can be:

[0010] In embodiments, T is:which each of R1and R2can be independently selected from hydrogen, carboxylic acid, which can be optionally substituted, malonic acid, succinic acid, glutamic acid, and adipic acid. In embodiments, the substituted carboxylic acid can be thioacetic acid or thiopropionic acid. In embodiments, T can be a urea of (a) an amino dicarboxylic acid or a derivative thereof and (b) an amino dicarboxylic acid or a derivative thereof, wherein (a) and (b) can be the same or different.

[0011] In embodiments, L can comprise a chain of atoms from about 3 atoms to about 30 atoms in length. In embodiments, L can comprise a chain of atoms from about 5 A to about 45 A in length. In embodiments, L can comprise a peptide. In embodiments, L can comprise one or more phenylalanine (Phe) residues, each of which is independently optionally substituted. In embodiments, L can comprise one or more Phe-Phe, in which at least one Phe is optionally substituted independently of the other Phe. In embodiments, L can comprise a polyoligoethylene glycol (POEGn), a polyethylene glycol (PEGn), or a mixture thereof, wherein n = 1-36. In embodiments, L can be releasable. In embodiments, L can be reductively cleavable. In embodiments, L can comprise a disulfide. In embodiments, L can be acid-cleavable. In embodiments, L can be enzyme-cleavable.

[0012] In embodiments, A can be XAV-939, PJ34 HC1, AG-14361, A-966492, G007-LK, UPF 1069, AZD2461, 3-Aminobenzamide, ME0328, NMS-P118, Stenoparib (E7449), NVP-TNKS656, WIKI4, Benzamide, BGP-152HC1, NU1025, Berberine chloride hydrate, IW55, BYK204165, Fluzoparib (SHR-3162), Picolinamide, Nesuparib, Licochalcone D, DR2313. MN 64, 4',5,7-Trimethoxyflavone, M2912, GeA-69, B102(PARP / HDAC-IN-l), Atamparib (RBN-2397), OUL232, Venadaparib (IDX-1197), HI-TOPK-032, 4-Hydroxyquinazoline, RBN012759, Saruparib (AZD53O5), AZD9574, or RK-287107.

[0013] In embodiments, Alb can be an albumin-binding group of the formula:which R4can be hydrogen, alkyl, or -O-.

[0014] Also provided is a conjugate of the formula T-L(AR)-A, in which T is a ligand that targets prostate-specific membrane antigen (PSMA); Lis a linker, which links T and A and T and Anand which is optionally linked to Alb; Alb is an albumin-binding group; AR is a radiotherapeutic or radioimaging agent; and A is an inhibitor of poly(ADP-ribose) polymerase (PARP).

[0015] Some conjugates can be of the structure:PSMA-RucaparibPSMA-Me2-S-S-JnJ

[0016] In view of the above, also provided is a pharmaceutical composition. The pharmaceutical composition can comprise an above-described conjugate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0017] In further view of the above, a method of treating a patient for a prostate-specific membrane antigen (PSMA)-expressing cancer or metastasis thereof is provided. The method comprises administering to the patient an effective amount of an above-described conjugate, or a pharmaceutically acceptable salt thereof, or an above-described pharmaceutical composition. In embodiment, the PSMA-expressing cancer can be prostate cancer, breast cancer, lung cancer, colorectal cancer, renal cell carcinoma, primary glioma, pancreatic ducal adenocarcinoma, thyroid cancer, hepatocellular cancer, or salivary gland tumor.

[0018] Further, cells with an increasing number of DSBs are more dependent on other DNA repair pathways, mainly the homologous recombination (HR) repair pathway. Cancer cells with HR deficiencies are, therefore, even more susceptible to PARP impairment of the base excision repair (BER) pathway.

[0019] The method can comprise administering to the patient:(i) the first above-described conjugate or a pharmaceutical composition comprising same,(ii) the second above-described conjugate or a pharmaceutical composition comprising same, or(iii) simultaneously or sequentially, in either order, (i) and a conjugate of the formula T-L-AR, wherein T is a ligand that targets PSMA, Lis a linker, which links T and AR, and AR is a radiotherapeutic or radioimaging agent.

[0020] In embodiments of the method, T in the conjugate of the formula T-L-AR can be:

[0021] In embodiments of the method, T can bewhich each of R1and R2can be independently selected from hydrogen, carboxylic acid, which is optionally substituted, malonic acid, succinic acid, glutamic acid, and adipic acid. In embodiments, the substituted carboxylic acid can be thioacetic acid or thiopropionic acid. In embodiments of the method, T in the conjugate of the formula T-L-AR can be a urea of (a) an amino dicarboxylic acid or a derivative thereof and (b) an amino dicarboxylic acid or a derivative thereof, wherein (a) and (b) can be the same or different.

[0022] In embodiments of the method, L can comprise a chain of atoms from about 3 atoms to about 30 atoms in length. In embodiments of the method, L can comprise a chain of atoms from about 5 A to about 45 A in length. In embodiments of the method, L can comprise a peptide. In embodiments of the method, L can comprise one or more phenylalanine (Phe) residues, each of which is independently optionally substituted. In embodiments of the method, L can comprise one or more Phe-Phe, in which at least one Phe is optionally substituted independently of the other Phe. In embodiments of the method, L can comprise a polyoligoethylene glycol (POEGn), a polyethylene glycol (PEGn), or a mixture thereof, wherein n = 1-36. In embodiments of the method, AR in the conjugate of the formula T-L-AR can comprise a radioisotope bound to a chelator selected from DOTA (1,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid) or a derivative thereof; TETA (1,4,8, 11-tetraazacy cl otetradecane- 1,4, 8, 11 -tetraacetic acid) or a derivative thereof; SarAr (l-N-(4-Aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-l,8-diamine or a derivative thereof; NOTA (l,4,7-triazacyclononane-l,4,7-triacetic acid) or a derivative thereof; NETA (4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[l,4,7]triazonan-l-yl) acetyc acid or a derivative thereof; TRAP (l,4,7-triazacyclononane-l,4,7-tris[methyl(2-carboxyethyl)phosphinic acid) or a derivative thereof; HBED (N,N0-bis(2-hydroxybenzyl)-ethylenediamine-N,N0-diacetic acid) or a derivative thereof; 2,3-HOPO (3-hydroxypyridin-2-one) or a derivative thereof; PCTA(3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-l(15),ll,13-triene-3,6,9,-triacetic acid) or a derivative thereof; DFO (desferri oxamine) or a derivative thereof; DTPA (diethylenetriaminepentaacetic acid) or a derivative thereof; OCTAPA (N,N0-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N, NO-diacetic acid) or a derivative thereof; or H2-MACROPA(N,N'-bis[(6-carboxy-2-pyridipmethyl]-4,13-diaza-18-crown-6) or a derivative thereof; H2dedpa (l,2-[[carboxy)-pyridin-2-yl]-methylamino]ethane or a derivative thereof; and EC20-head comprising P-l-diaminopropionic acid, aspartic acid, and cysteine.

[0023] In embodiments of the method, the radioisotope can be selected from18F,44Sc,47Sc,52Mn,55Co,64Cu,67CU,67Ga,68Ga,86Y,89Zr,90Y, "mTc,inIn,114mIn,117mSn,124I,125I,131I,149Tb,153Sm,152Tb,155Tb,161Tb,177Lu,186Re,188Re,212Pb,212Bi,213Bi,223Ra,224Ra,225Ab,225Ac, and227Th.

[0024] In embodiments, the method can further comprise treating the patient with external beam radiation.

[0025] In embodiments of the method, the cancer can be prostate cancer.FIGURES

[0026] FIGs. 1 A-IJ presents representative A groups in the instant conjugates.DESCRIPTION

[0027] Provided are PSMA-targeted PARP inhibitors comprising conjugates of the formula T-L(Alb)-A in which: T is a ligand that targets prostate-specific membrane antigen (PSMA); A is an inhibitor of poly(ADP-ribose) polymerase (PARP); L is a linker, which links T and A; Alb is an optional albumin-binding group, in which case L is linked to Alb; with the proviso that A is not Inhibitoren, Rucaparib, Olaparib, Niraparib, Veliparib, Iniparib, Pamiparib, EB-47, or Talazoparib.

[0028] In embodiments, T can be:

[0029] In embodiments, T is:which each of R1and R2can be independently selected from hydrogen, carboxylic acid, which is optionally substituted, malonic acid, succinic acid, glutamic acid, and adipic acid. In embodiments, the substituted carboxylic acid can be thioacetic acid or thiopropionic acid. In embodiments, T can be a urea of (a) an amino dicarboxylic acid or a derivative thereof and (b) an amino dicarboxylic acid or a derivative thereof, wherein (a) and (b) can be the same or different.

[0030] In embodiments, L can comprise a chain of atoms from about 3 atoms to about 30 atoms in length. In embodiments, L can comprise a chain of atoms from about 5 A to about 45 A in length. In embodiments, L can comprise a peptide. In embodiments, L can comprise one or more phenylalanine (Phe) residues, each of which is independently optionally substituted. In embodiments, L can comprise one or more Phe-Phe, in which at least one Phe is optionally substituted independently of the other Phe. In embodiments, L can comprise a polyoligoethylene glycol (POEGn), a polyethylene glycol (PEGn), or a mixture thereof, wherein n = 1-36. In embodiments, L can be releasable. In embodiments, L can be reductively cleavable. In embodiments, L can comprise a disulfide. In embodiments, L can be acid-cleavable. In embodiments, L can be enzyme-cleavable.

[0031] In embodiments, A can be XAV-939, PJ34 HC1, AG-14361, A-966492, G007-LK, UPF 1069, AZD2461, 3-Aminobenzamide, ME0328, NMS-P118, Stenoparib (E7449), NVP-TNKS656, WIKI4, Benzamide, BGP-152HC1, NU1025, Berberine chloride hydrate, IW55, BYK204165, Fluzoparib (SHR-3162), Picolinamide, Nesuparib, Licochalcone D, DR2313. MN 64, 4',5,7-Trimethoxyflavone, M2912, GeA-69, B102(PARP / HDAC-IN-l), Atamparib (RBN-2397), OUL232, Venadaparib (IDX-1197), HI-TOPK-032, 4-Hydroxyquinazoline, RBN012759, Saruparib (AZD53O5), AZD9574, or RK-287107. Representative A structures can be found in FIGs. 1A-1J.

[0032] Olaparib is approved as a PARP inhibitor for use in the treatment of ovarian cancer, breast cancer, pancreatic cancer and prostate cancer in certain patient subgroups. In ovarian cancer, olaparib is used for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopiantube or primary peritoneal cancer who are in complete or partial response to first-line platinum based chemotherapy; for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy; and for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

[0033] Niraparib is approved as a PARP inhibitor for the maintenance treatment of adult patients with advanced or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy; and for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a deleterious or suspected deleterious BRCA mutation, or genomic instability and who have progressed more than six months after response to the last platinum-based chemotherapy.

[0034] Notably, niraparib is the only PARP inhibitor, and small molecule, approved for front-line maintenance treatment in patients with tumors irrespective of HR status (typically measured as HR deficiency score). In a Phase 3 clinical trial, the PRIMA study, participants with advanced ovarian cancer after having received platinum therapy, the group of participants with low HRD score traditionally not selected for treatment with a PARP inhibitor also showed benefits with niraparib treatment.

[0035] In embodiments, Alb can be an albumin-binding group of the formula:. In embodiments, Alb can be linked to L by an NR4group, in which R4can be hydrogen, alkyl, or -O-.

[0036] Also provided can be a conjugate of the formula T-L(AR)-A, in which T can be a ligand that targets prostate-specific membrane antigen (PSMA); L can be a linker, which links T and A and T and AR and which is optionally linked to Alb; Alb can be an albumin-binding group;AR can be a radiotherapeutic or radioimaging agent; and A is an inhibitor of poly(ADP-ribose) polymerase (PARP).

[0037] Some conjugates can be of the structure:PSMA-Me2-S-S-JnJ

[0038] The conjugates can be synthesized in accordance with methods well-known in the art. Various methods are exemplified herein.

[0039] In view of the above, also provided is a pharmaceutical composition. The pharmaceutical composition can comprise an above-described conjugate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutical formulations comprising a conjugate may be prepared in accordance with methods well-known in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 19thed. (Maack Pub. Co., Easton, PA (1995)). Formulation of the conjugates as pharmaceutically acceptable salts can be appropriate.

[0040] Further in view of the above, a method of treating a patient for a cancer or metastasis thereof, wherein the cancer expresses prostate-specific membrane antigen (PSMA), is provided.

[0041] In embodiments of the method, the cancer can be prostate cancer, breast cancer, lung cancer, colorectal cancer, renal cell carcinoma, primary glioma, pancreatic ducal adenocarcinoma, thyroid cancer, hepatocellular cancer, or salivary gland tumor. In embodiments of the method, the cancer can be prostate cancer.

[0042] The methods can comprise administering to the patient:(i) the first above-described conjugate or a pharmaceutical composition comprising same,(ii) the second above-described conjugate or a pharmaceutical composition comprising same, or(iii) simultaneously or sequentially, in either order, (i) and a conjugate of the formula T-L-AR, wherein T is a ligand that targets PSMA, is a linker, which links T and AR, and AR is a radiotherapeutic or radioimaging agent.

[0043] In certain embodiments, the method can further comprise simultaneously or sequentially, in either order, treating the patient with external beam radiotherapy. In embodiments, the method can further comprise simultaneously or sequentially, in either order, treating the patient with an effective amount of a conjugate of the formula T-LXR, or a pharmaceutically acceptable salt thereof, wherein T is a ligand (radical thereof) that binds prostate-specific membrane antigen (PSMA), Lis a linker, and XR is a radiotherapeutic or radioimaging agent, wherein the conjugate or pharmaceutically acceptable salt thereof can be formulated as a pharmaceutical composition,which further comprises a pharmaceutically acceptable carrier.

[0044] In embodiments, XR can be a radiotherapeutic agent comprising a radioisotope bound to a chelator selected from DOTA(l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid) or a derivative thereof; TETA(l,4,8,ll-tetraazacyclotetradecane-l,4,8,ll-tetraacetic acid) or a derivative thereof; SarAr (l-N-(4-Aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-l,8-diamine or a derivative thereof; NOTA (l,4,7-triazacyclononane-l,4,7-triacetic acid) or a derivative thereof; NETA (4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[l,4,7]triazonan-l-yl) acetyc acid or a derivative thereof; TRAP (l,4,7-triazacyclononane-l,4,7-tris[methyl(2-carboxyethyl)phosphinic acid) or a derivative thereof; HBED (N,N0-bis(2-hydroxybenzyl)-ethylenediamine-N, NO-diacetic acid) or a derivative thereof; 2,3-HOPO (3-hydroxypyridin-2-one) or a derivative thereof; PCTA(3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15), 11, 13-triene-3, 6, 9, -triacetic acid) or a derivative thereof; DFO (desferrioxamine) or amderivative thereof; DTPA (diethylenetriaminepentaacetic acid) or a derivative thereof;OCTAPA (N,N0-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N, NO-diacetic acid) or a derivative thereof; or H2-MACROPA (N,N'-bis[(6-carboxy-2-pyridipmethyl]-4,13-diaza-18-crown-6) or a derivative thereof; H2dedpa (l,2-[[carboxy)-pyridin-2-yl]-methylamino]ethane or a derivative thereof; and EC20-head comprising P-l-diaminopropionic acid, aspartic acid, and cysteine. In embodiments, the radioisotope can be selected from18F,44Sc,47Sc,52Mn,?5Co,64Cu,67Cu,67Ga, 68Ga, 86Y, 89Zr, 90Y, 99mTc, U lin, 114mln, 117mSn, 1241, 1251, 1311, 149Tb, 153Sm, 152Tb, 155Tb, 161Tb,177Lu,186Re,188Re,212Pb,212Bi,213Bi,223Ra,224Ra,225Ab,225Ac, and227Th.

[0045] The term “administering,” and its formatives, generally refers to any and all means of introducing conjugates to the patient including, but not limited to, by oral, intravenous, intramuscular, subcutaneous, transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and like routes of administration.

[0046] An “effective amount” of an above-described pharmaceutical composition can be determined by comparing in vitro activity and in vivo activity in animal models. Methods of the extrapolation of effective dosages in mice and other animals to human subjects are known in the art. Indeed, the effective amount can vary significantly depending on the condition of the patient, the cancer type being treated, how advanced the pathology is, the route of administration of the compound and tissue distribution, and the possibility of co-usage of other therapeutic treatments (such as radiation therapy or additional drugs in combination therapies). The amount will ultimately be at the discretion of the attendant physician, clinician, or otherwise.

[0047] In embodiments of the method, the cancer can be a solid tumor. In embodiments of the method, the cancer can be a tumor with tumor-associated macrophages. In embodiments of the method, the method further comprises treating the patient with immunotherapy or radiotherapy.

[0048] In embodiments of the method, T in the conjugate of the formula T-L-AR is:

[0049] In embodiments of the method, T is:which each of R1and R2can be independently selected from hydrogen, carboxylic acid, which is optionally substituted, malonic acid, succinic acid, glutamic acid, and adipic acid. In embodiments, the substituted carboxylic acid can be thioacetic acid or thiopropionic acid. In embodiments of the method, T in the conjugate of the formula T-L-AR can be a urea of (a) an amino dicarboxylic acid or a derivative thereof and (b) an amino dicarboxylic acid or a derivative thereof, wherein (a) and (b) can be the same or different.

[0050] In embodiments of the method, L comprises a chain of atoms from about 3 to about 30 atoms, 3 to about 30 atoms, about 3 to 30 atoms, or 3 to 30 atoms. In certain embodiments, L comprises 3 to 25 atoms, 3 to 20 atoms, 3 to 15 atoms, or 5 to 15 atoms.

[0051] In embodiments of the method, L comprises a chain of atoms from about 5 A to about 45 A in length. In embodiments of the method, L comprises a peptide. In embodiments of the method, L comprises one or more phenylalanine (Phe) residues, each of which is independently optionally substituted. In embodiments of the method, L comprises one or more Phe-Phe, in which at least one Phe is optionally substituted independently of the other Phe. In embodiments of the method, L comprises a polyoligoethylene glycol (POEGn), a polyethylene glycol (PEGn), or a mixture thereof, wherein n = 1-36.

[0052] In embodiments of the method, AR in the conjugate of the formula T-L-AR comprises a radioisotope bound to a chelator selected from DOTA (1,4,7, 10-tetraazacyclododecane- 1.4.7.10-tetraacetic acid) or a derivative thereof; TETA (1,4,8, 11-tetraazacy cl otetradecane- 1.4.8.11 -tetraacetic acid) or a derivative thereof; SarAr (l-N-(4-Aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-l,8-diamine or a derivative thereof; NOTA (1,4,7-triazacyclononane-l,4,7-triacetic acid) or a derivative thereof; NETA (4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[l,4,7]triazonan-l-yl) acetic acid or a derivative thereof; TRAP (l,4,7-triazacyclononane-l,4,7-tris[methyl(2-carboxyethyl)phosphinic acid) or a derivative thereof; HBED (N,N0-bis(2-hydroxybenzyl)-ethylenediamine-N, NO-diacetic acid) or a derivative thereof; 2,3-HOPO (3-hydroxypyridin-2-one) or a derivative thereof; PCTA (3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-l(15),ll,13-triene-3,6,9,-triacetic acid) or a derivative thereof; DFO (desferri oxamine) or a derivative thereof; DTPA (di ethylenetriaminepentaaceticacid) or a derivative thereof; OCTAPA (N,N0-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N, NO-diacetic acid) or a derivative thereof; or H2-MACROPA(N,N'-bis[(6-carboxy-2-pyridipmethyl]-4, 13 -diaza- 18-crown-6) or a derivative thereof; H2dedpa (l,2-[[carboxy)-pyridin-2-yl]-methylamino]ethane or a derivative thereof; and EC20-head comprising P-l-diaminopropionic acid, aspartic acid, and cysteinecan be is selected from18F,44Sc,47Sc,52Mn,55Co,64Cu,67CU,67Ga,68Ga,86Y,89Zr,90Y, "mTc,niIn,114mIn,117mSn,1241,125I,131I,149Tb,153Sm,152Tb,155Tb,161Tb,177LU,186Re,188Re,212Pb,212Bi,213Bi,223Ra,224Ra,225Ab,225Ac, and227Th.

[0053] In embodiments, the method further comprises treating the patient with external beam radiation.EXAMPLESExample 1: Synthesis of compound 2

[0054] MC-Val-Cit-PAB-OH (1) (0.087 mmol, 50 mg) is suspended in DMF (500pL) and heated to 80 °C to dissolve all solids. After cooling to 0 °C, thionyl chloride (50 pL) is added portion wise. Following the addition, the reaction is held at 0 °C for 2-5 h. Reaction progression is monitored through LCMS. The crude reaction mixture is purified by column chromatography using 5% DCM methanol mixture as mobile phase to obtain the pure product 2 as yellow solid. (31 mg, yield 60%, tR = 3.980 min). Compound 2 LCMS (+ESI) calcd for [M+H]+(C28H39C1N6O6)+591.3 found 591.3.Example 2: Synthesis of compound 3 (activation of AG-14361)

[0055] In a small vial, the tertiary amine AG-14361 (leq) and 2 N-[(lS)-l-[[(lS)-l-[[4- (chloromethyl)phenyl]carbamoyl]-4-ureido-butyl]carbamoyl]-2-methyl-propyl]-6-(2,5-dioxopyrrol-l-yl)hexanamide (1.1 eq) are combined in DMF at room temperature. To thesolution is added 0.5 eq of tetrabutyl ammonium iodide followed by N,N-diisopropylethylamine (2.5 eq) and the mixture stirred until all starting material amine is consumed or until decomposition is observed by LCMS (3-48 h). The mixture is diluted with 1.5 mL of DMF and is injected directly on HPLC for purification eluting with 20-60% acetonitrile:0.1% formic acid in water to afford the quaternary salt product. The pure product 3 is obtained as white solid (yield 45%, tR = 3.980 min).Example 3: Synthesis of conjugate 5

[0056] Compound 3 (leqv) is dissolved in DMSO (ImL). The reaction mixture is degassed continuously with Argon. Compound 4 (leqv) is dissolved in DMSO and added to the reaction mixture. LCMS is monitored after Ih. After completion of the reaction the product 5 is purified using reverse phase HPLC using 10 mmolar ammonium acetate (pH=5) and acetonitrile. Pure fractions of 5 are collected using automatic fraction collector, acetonitrile is evaporated under reduced pressure and after lyophilization pure bioconjugate 5 is obtained.Example 4: Synthesis of Linker (9) and Conjugation with Compound (10):

[0057] In a typical preparation, a solution of 2-(pyridine-2-yl-disulfanyl) ethanol (2.0 g, 8.94 mmol), hydroxybenzotriazole (HOBT, 1.58 g, 11.71 mmol), and triethylamine (TEA, 1.25 mL, 8.94 mmol) in acetonitrile (CHUN, 35 mL) is cooled to 0 °C under an inert atmosphere.Triphosgene (5.98 mmol) is then added to the solution. The reaction mixture is allowed to warm to room temperature and is stirred for approximately 24 hours. Upon completion, the solid product is fdtered, washed with acetonitrile, and dried under vacuum at room temperature to yield the heterobifunctional linker (9) as a pale white solid with an approximate yield of 86%. In the subsequent conjugation step, linker (9) (0.027 g, 0.078 mmol) is added to a solution of compound (10) (0.025 g, 0.052 mmol) and 4-dimethylaminopyridine (DMAP, 0.006 g, 0.052 mmol) in dichloromethane (DCM) at room temperature under a nitrogen atmosphere. The reaction mixture is stirred at reflux temperature for 3 hours. The reaction progress may be monitored by liquid chromatography-mass spectrometry (LCMS) (Scheme 1).

[0058] After 3 hours, the reaction is quenched by adding additional DCM, and the product is purified by column chromatography using a mobile phase comprising 5% methanol in DCM.

[0059] The pure product is collected and dried under reduced pressure to yield the final conjugated compound (11).SCHEME 1. Synthesis of Linker 9 and Compound 11Example 5: Synthesis of conjugate (12)

[0060] In a typical preparation, Compound (11) (1 equivalent) is dissolved in dimethyl sulfoxide (DMSO, 1 mL), and 4-dimethylaminopyridine (DMAP, 1 equivalent) is added to the solution. The reaction mixture is then degassed by continuously bubbling argon. Separately, compound (8) (1 equivalent) is dissolved in DMSO and added to the reaction mixture in three portions over a period of 1 hour, with 20-minute intervals between each addition (Scheme 2). The progress of the reaction is monitored by liquid chromatography-mass spectrometry (LCMS). Upon completion, the reaction mixture is purified by reverse-phase high-performance liquid chromatography (HPLC) using a mobile phase of 10 mM ammonium acetate (pH 5) and acetonitrile. Pure fractions containing bioconjugate (12) are collected using an automatic fraction collector. Acetonitrile is evaporated under reduced pressure, and the product is lyophilized toyield the pure bioconjugate (12).SCHEME 2. Synthesis of Compound (12)Example 6: Method for Evaluating Double-Stranded DNA Break Repair in PSMA- Expressing Cells Using Bioconjugates

[0061] In one embodiment, LNCaP (PSMA+), DU145 (PSMA+), and PC-3 (PSMA ) cell lines are cultured in T-75 flasks in RPMI 1640 medium, supplemented with 1% penicillin-streptomycin and 10% fetal bovine serum (FBS), at 37 °C in a humidified incubator containing 5% CO2. For evaluation, the cells are seeded onto 6 cm dishes containing cover glasses at a density of approximately 4 x 105cells per dish. Each well receives 2 mL of fresh medium.

[0062] A solution of five different compounds — 5 and AG-14361 are prepared at three concentrations (10 nM, 1 nM, and 0.1 nM). To each well, 2 pL of the corresponding compound solution is added. The cells are incubated for 1 hour at room temperature. After incubation, the cells are exposed to ionizing radiation (IR) at 2 Gy, followed immediately by replacement of the medium with fresh RPMI 1640. The cells are allowed to recover under standard culture conditions for an additional 6 hours to facilitate DNA repair.

[0063] Following the recovery period, cells are gently rinsed with IX PBS and fixed with 3.7% formaldehyde for approximately 20 minutes at ambient temperature. The cells are then washed three times with IX PBS, followed by permeabilization with a 0.2% Triton X-100 solution for 5 minutes at room temperature. After three additional PBS washes, cells are blocked with 5% milk in IX PBS for 1 hour at room temperature.

[0064] The cells are then incubated overnight at 4 °C with a primary antibody [Phospho-Histone H2A.X (Serl39) (20E3)], diluted at 1:400 in a 5% milk / PBS solution, with 100 pL applied to each cover glass. The following day, the cells are rinsed three times with IX PBS, followed by the addition of a secondary antibody solution (anti-rabbit Alexa Fluor, diluted 1 :2000) and DAPI (final concentration of 1 pg / mL) in 5% milk / PBS. The cells are incubated with this solution for 1 hour at room temperature, washed three times with IX PBS, and then mounted onto glass slides using ProLong® Antifade Kit (Invitrogen).

[0065] Images are captured under oil immersion using an inverted fluorescence microscope (60x objective, Nikon Instruments) with the NIS Elements software. The anticipated results are that cells treated with Compounds 5 and AG-14361 at 1 nM in PSMA-positive cell lines LNCaP and DU 145 exhibit a significant increase in DNA double-strand break foci, suggesting impaired DNA repair. The lack of significant effect in PSMA-negative PC -3 cells highlights the specificity of Compounds 5 and AG-14361 for PSMA-positive cell lines.Example 7: Method for Evaluating Tumor Response to Compounds in LNCaP Xenograft Model with Ionizing Radiation Therapy

[0066] In one embodiment, five-week-old male nu / nu mice are inoculated subcutaneously with LNCaP cells (5.0 x 106cells / mouse) in a mixture of 50 pL phosphate-buffered saline (PBS) and 50 pL Matrigel on the shoulder region. Tumor growth is measured bi-dimensionally every two days using a caliper, with body weights monitored concurrently. Tumor volume (mm3) is calculated according to the formula: 0.5 x L x W2, where L is the longest axis and W is the perpendicular axis in millimeters.

[0067] When tumors reach a volume of approximately 150-200 mm3, mice are assigned to one of four treatment groups as follows:• Group 1 (Untreated): Tumor-bearing mice receive no treatment (n=5).• Group 2 (Radiation Only): Tumor-bearing mice receive fractionated ionizing radiation (FIR) at 5 Gy per fraction (n=5).• Group 3 (Radiation + Compound 5): Tumor-bearing mice receive 10 nmol of Compound 5 administered via intravenous injection 1 hour prior to FIR (n=5).• Group 4 (Radiation + AG- 14361): Tumor-bearing mice receive 10 nmol of Compound AG-14361 administered via intravenous injection 1 hour prior to FIR (n=5).

[0068] For Groups 3 and 4, Compounds 5 and AG-14361 respectively are administered 1 hour before radiation exposure. External beam radiation therapy is administered to all groups as applicable, using a dose of 5 Gy per fraction. Tumor response to treatments is monitored by measuring tumor volume and body weight over the course of the experiment. This method assesses the therapeutic efficacy of Compounds 5 and AG-14361in combination with radiation therapy.

[0069] Radiolabeling and Evaluation of Therapeutic Efficacy of [177Lu] Lu-PSMA-617 Conjugate in Combination with Compounds 5 and AG-14361 in LNCaP Tumor-Bearing Mice:

[0070] Radiolabeling Process: In a representative embodiment, PSMA-617 is dissolved in ammonium acetate buffer (10 mM, pH 6.0) and radiolabeled with [177Lu]Lu 3+ obtained from a commercial source such as the National Isotope Development Center, yielding a radiolabeled [177LU]LU-PSMA-617 conjugate.

[0071] Animal Husbandry Conditions: Mice are housed with ad libitum access to standard rodent chow and water, maintained on a5-hour light-dark cycle. All procedures are approved by the Purdue Animal Care and Use Committee in compliance with institutional and regulatory standards for animal care.

[0072] Tumor Model Development: Athymic nude mice are subcutaneously inoculated with 5 * 105LNCaP cells, delivered in a mixture of 100 pL PBS and Matrigel at a 1 : 1 ratio, on the shoulder region to establish tumor growth.

[0073] Radiotherapy and Treatment Protocol: Mice with established LNCaP tumors are randomly assigned to control and treatment groups to ensure balanced starting tumor volumes across groups. Each cohort receives a single intravenous administration of either vehicle or vehicle combined with the [177Lu]Lu-PSMA-617 conjugate on day 0. The treatment groups are as follows:• Group 1: Untreated control group, receiving only vehicle.• Group 2: [177Lu]Lu-PSMA-617 treatment group, receiving 9.25 MBq of radiolabeled PSMA-617 .• Group 3: [177Lu]Lu-PSMA-617 with Compound 5, receiving 9.25 MBq of [177Lu]Lu-PSMA-617 and a daily dose of 10 nmol Compound 5 for 28 consecutive days.• Group 4: [177Lu]Lu-PSMA-61 with Compound AG-14361, receiving 9.25 MBq of [177Lu]Lu-PSMA-617 and a daily dose of 10 nmol Compound AG-14361 for 28 consecutive days.

[0074] Each treatment cohort (except the untreated control group) receives a dose of 9.25 MBq of [177LU]LU-PSMA-617.Example 8: Tumor Measurement and Endpoints:

[0075] Tumor growth is monitored bi-dimensionally with calipers in two perpendicular directions. Mice are euthanized upon reaching predefined endpoint criteria in accordance with Institutional Animal Care and Use Committee regulations. Tumor inhibition results reveal that the combination of [177Lu]Lu-PSMA-617 and Compounds 5 andAG- 14361 achieves approximately 81% inhibition in tumor growth relative to the untreated control group, with no significant body weight loss observed throughout the study.Example 7: Method for Evaluating Tumor Response to Compounds in LNCaP Xenograft Model with Ionizing Radiation Therapy

[0076] In one embodiment, five-week-old male nu / nu mice are inoculated subcutaneously with LNCaP cells (5.0 x 106cells / mouse) in a mixture of 50 pL phosphate-buffered saline (PBS)and 50 pL Matrigel on the shoulder region. Tumor growth is measured bi-dimensionally every two days using a caliper, with body weights monitored concurrently. Tumor volume (mm3) is calculated according to the formula: 0.5 x L x W2, where L is the longest axis and W is the perpendicular axis in millimeters.

[0077] When tumors reach a volume of approximately 150-200 mm3, mice are assigned to one of four treatment groups as follows:Group 1 (Untreated): Tumor-bearing mice receive no treatment (n=5).Group 2 (Radiation Only): Tumor-bearing mice receive fractionated ionizing radiation (FIR) at 5 Gy per fraction (n=5).Group 3 (Radiation + Compound (12)): Tumor-bearing mice receive 10 nmol of Compound 12 administered via intravenous injection 1 hour prior to FIR (n=5).Group 4 (Radiation + Compound (15)): Tumor-bearing mice receive 10 nmol of Compound 15 administered via intravenous injection 1 hour prior to FIR (n=5).

[0078] For Groups 3 and 4, compounds (12) and (15), respectively, are administered 1 hour before radiation exposure. External beam radiation therapy is administered to all groups as applicable, using a dose of 5 Gy per fraction. Tumor response to treatments is monitored by measuring tumor volume and body weight over the course of the experiment. This method assesses the therapeutic efficacy of compounds (12) and (15) in combination with radiation therapy.Example 9: Radiolabeling and Evaluation of Therapeutic Efficacy of [177Lu] Lu-PSMA-617 Conjugate in Combination with Compounds (12) and (15) in LNCaP Tumor-Bearing Mice

[0079] Radiolabeling Process: In a representative embodiment, PSMA-617 (16) is dissolved in ammonium acetate buffer (10 mM, pH 6.0) and radiolabeled with [177Lu]Lu3+obtained from a commercial source such as the National Isotope Development Center, yielding a radiolabeled [177Lu]Lu-PSMA-617 (16) conjugate.<&

[0080] Animal Husbandry Conditions: Mice are housed with ad libitum access to standard rodent chow and water, maintained on a 12-hour light-dark cycle. All procedures are approved

[0081] by the Purdue Animal Care and Use Committee in compliance with institutional and regulatory standards for animal care.

[0082] Tumor Model Development: Athymic nude mice are subcutaneously inoculated with 5 x io5LNCaP cells, delivered in a mixture of 100 pL PBS and Matrigel at a 1 : 1 ratio, on the shoulder region to establish tumor growth.

[0083] Radiotherapy and Treatment Protocol: Mice with established LNCaP tumors are randomly assigned to control and treatment groups to ensure balanced starting tumor volumes across groups. Each cohort receives a single intravenous administration of either vehicle or vehicle combined with the [177Lu]Lu-PSMA-617 (16) conjugate on day 0. The treatment groups are as follows:Group 1 : Untreated control group, receiving only vehicle.Group 2: [177Lu]Lu-PSMA-617 (16) treatment group, receiving 9.25 MBq of radiolabeled PSMA-617 (16).Group 3: [177Lu]Lu-PSMA-617 (16) with Compound (12), receiving 9.25 MBq of [177Lu]Lu-PSMA-617 (16) and a daily dose of 10 nmol Compound (12) for 28 consecutive days.Group 4: [177Lu]Lu-PSMA-617 (16) with Compound (15), receiving 9.25 MBq of [177Lu]Lu-PSMA-617 (16) and a daily dose of 10 nmol Compound (15) for 28 consecutive days.

[0084] Each treatment cohort (except the untreated control group) receives a dose of 9.25 MBq of [177Lu]Lu-PSMA-617 (16).

[0085] Tumor Measurement and Endpoints: Tumor growth is monitored bi-dimensionally with calipers in two perpendicular directions. Mice are euthanized upon reaching predefined endpoint criteria in accordance with Institutional Animal Care and Use Committee regulations. Tumor inhibition results reveal that the combination of [177Lu]Lu-PSMA-617 (16) and Compounds (12) and 15 achieves approximately 81% inhibition in tumor growth relative to the untreated control group, with no significant body weight loss observed throughout the study.

[0086] Survival Analysis and Efficacy Results: The combination therapy with [177Lu]Lu-PSMA-617 (16) and compounds (12) and (15) demonstrates a notable survival benefit, extending survival by relative to control.Example 10: Survival Analysis and Efficacy Results:

[0087] The combination therapy with [177Lu]Lu-PSMA-617 and Compounds 5 and AG-14361 demonstrates a notable survival benefit, extending survival by relative to control.Definitions

[0088] The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range.

[0089] Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as ifeach numerical value and sub-range were explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0090] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading may occur within or outside of that section.

[0091] By “half-life” is meant the time for one-half of the active agent to be eliminated through metabolism or excretion. By “hepatic first-pass metabolism” is meant the propensity of the active agent to be metabolized upon first contact with the liver, i.e., during the active agent’s first pass through the liver. By “volume of distribution” is meant the distribution, alone or in further combination with the degree of retention, of the active agent throughout the various compartments of a subject, e g., intracellular spaces, extracellular spaces, tissues, and organs.

[0092] Various modifications and variations of the described compositions, methods, and uses of the technology will be apparent to those skilled in the art without departing from the scope and spirit of the technology as described. Although the technology has been described in connection with specific exemplary embodiments, 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 following claims.

[0093] All publications and patents mentioned herein are incorporated by reference in their entireties for all purposes. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should beconsidered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.Enumerated Embodiments (EE)

[0094] The following list of enumerated embodiments presents claims with multiply dependent claims depending from multiply dependent claims for presentation in those jurisdictions where such dependencies are allowed as well as additional claims, which may be presented during the examination of the application or any divisional or continuation thereof.

[0095] EE 1. A conjugate of the formula:T-L(Alb)-A(I)in which:T is a ligand that targets prostate-specific membrane antigen (PSMA);A is an inhibitor of poly(ADP-ribose) polymerase (PARP), with the proviso that A is not Inhibitoren, Rucaparib, Olaparib, Niraparib, Veliparib, Iniparib, Pamiparib, EB-47, or Talazoparib;Lis a linker, which links T and A; andAlb is an optional albumin-binding group, in which case L is linked to Alb.

[0096] EE 2. The conjugate of EE 1, wherein T is:

[0101] EE 3. The conjugate of EE 1, wherein T is:which each of R1and R2is independently selected from hydrogen, carboxylic acid, which is optionally substituted, malonic acid, succinic acid, glutamic acid, and adipic acid.

[0102] EE 4. The conjugate of EE 3, wherein the substituted carboxylic acid is thioacetic acid or thiopropionic acid.

[0103] EE 5. The conjugate of any one of EE 1 - EE 4, wherein T is a urea of (a) an amino di carboxylic acid or a derivative thereof and (b) an amino di carboxylic acid or a derivative thereof, wherein (a) and (b) can be the same or different.

[0104] EE 6. The conjugate of any one of EE 1 - EE5, wherein L comprises a chain of atoms from about 3 atoms to about 30 atoms in length.

[0105] EE 7. The conjugate of any one of EE 1 - EE 6, wherein L comprises a chain of atoms from about 5 A to about 45 A in length.

[0106] EE 8. The conjugate of any one of EE 1 - EE 7, wherein L comprises a peptide.

[0107] EE 9. The conjugate of EE 8, wherein L comprises one or more phenylalanine (Phe) residues, each of which is independently optionally substituted.

[0108] EE 10. The conjugate of EE 9, wherein L comprises one or more Phe-Phe, in which at least one Phe is optionally substituted independently of the other Phe.

[0109] EE 11. The conjugate of any one of EE 1 - EE10, wherein L comprises a polyoligoethylene glycol (POEGn), a polyethylene glycol (PEGn), or a combination thereof, wherein n = 1-36.

[0110] EE 12. The conjugate of any one of EE 1 - EE11, wherein L is reductively cleavable.

[0111] EE 13. The conjugate of any one of EE 1 - EE 12, wherein L comprises a disulfide.

[0112] EE 14. The conjugate of any one of EE 1 - EE 13, wherein L is acid-cleavable.

[0113] EE 15. The conjugate of any one of EE 1 - EE 13, wherein L is enzyme-cleavable.

[0114] EE 16. The conjugate of any one of EE 1 - EE 15, wherein L is releasable.

[0115] EE 17. The conjugate of any one of EE 1 - EE 16, wherein A is XAV-939, PJ34 HC1, AG-14361, A-966492, G007-LK, UPF 1069, AZD2461, 3 -Aminobenzamide, ME0328, NMS- Pl 18, Stenoparib (E7449), NVP-TNKS656, WIKI4, Benzamide, BGP-152HC1, NU1025, Berberine chloride hydrate, JW55, BYK204165, Fluzoparib (SHR-3162), Picolinamide, Nesuparib, Licochalcone D, DR2313. MN 64, 4',5,7-Trimethoxyflavone, M2912, GeA-69, B102(PARP / HDAC-IN-l), Atamparib (RBN-2397), OUL232, Venadaparib (IDX-1197), HI-TOPK-032, 4-Hydroxyquinazoline, RBN012759, Saruparib (AZD5305), AZD9574, or RK-287107.

[0116] EE 18. A conjugate having one of the structures:PSMA-Nedisertib orPSMA-Me2-S-S-JnJ

[0117] EE 19. A conjugate of the formula T-L(AR)-A, in which:T is a ligand that targets prostate-specific membrane antigen (PSMA);L is a linker, which links T and A and T and Anand which is optionally linked to Alb; Alb is an albumin-binding group;AR is a radiotherapeutic or radioimaging agent; andA is an inhibitor of poly(ADP -ribose) polymerase (PARP).

[0118] EE 20. The conjugate of EE 19, wherein Alb is an albumin-binding group of the formula:

[0119] EE 21. A pharmaceutical composition comprising a conjugate of any one of EE 1 -EE 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0120] EE 22. A pharmaceutical composition comprising a conjugate of EE 19 or EE 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0121] EE 23. A method of administering to a patient for a cancer or metastasis thereof, wherein the cancer expresses prostate-specific membrane antigen (PSMA), which method comprises administering to the patient:(i) a conjugate of any one of EE 1- EE 19 or a pharmaceutical composition of claim 21,(ii) a conjugate of EE 20 or a pharmaceutical composition of EE 22, or(iii) simultaneously or sequentially, in either order, (i) and a conjugate of the formula T-L-AR, wherein T is a ligand that targets PSMA, Lis a linker, which links T and AR, and AR is a radiotherapeutic or radioimaging agent,wherein the patient is treated and / or imaged for the cancer or metastasis thereof.

[0122] EE 24. The method of EE 23, wherein T in the conjugate of the formula T-L-AR is:

[0123] EE 25. The method of EE 23, wherein T is:which each of R1and R2is independently selected from hydrogen, carboxylic acid, which is optionally substituted, malonic acid, succinic acid, glutamic acid, and adipic acid.

[0124] EE 26. The method of EE 25, wherein the substituted carboxylic acid is thioacetic acid or thiopropionic acid.

[0125] EE 27. The method of any one of EE 23 - EE 26, wherein T in the conjugate of the formula T-L-AR is a urea of (a) an amino dicarboxylic acid or a derivative thereof and (b) an amino dicarboxylic acid or a derivative thereof, wherein (a) and (b) can be the same or different.

[0126] EE 28. The method of any one of EE 23 - EE 27, wherein L comprises a chain of atoms from about 3 atoms to about 30 atoms in length.

[0127] EE 29. The method of any one of EE 23 - EE 28, wherein L comprises a chain of atoms from about 5 A to about 45 A in length.

[0128] EE 30. The method of any one of EE 23 - EE 29, wherein L comprises a peptide.

[0129] EE 31. The method of EE 30, wherein L comprises one or more phenylalanine (Phe) residues, each of which is independently optionally substituted.

[0130] EE 32. The method of EE 31, wherein L comprises one or more Phe-Phe, in which at least one Phe is optionally substituted independently of the other Phe.

[0131] EE 33. The method of any one of EE 23 - EE 29, wherein L comprises a polyoligoethylene glycol (POEGn), a polyethylene glycol (PEGn), or a mixture thereof, wherein n = 1-36.

[0132] EE 34. The method of any one of EE 23 - EE 33, wherein AR in the conjugate of the formula T-L-AR comprises a radioisotope bound to a chelator selected from DOTA (1,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid) or a derivative thereof; TETA (1,4,8, 11-tetraazacy cl otetradecane- 1,4, 8, 11 -tetraacetic acid) or a derivative thereof; SarAr (l-N-(4-Aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-l,8-diamine or a derivative thereof; NOTA (l,4,7-triazacyclononane-l,4,7-triacetic acid) or a derivative thereof; NETA (4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[l,4,7]triazonan-l-yl) acetyc acid or a derivative thereof; TRAP (l,4,7-triazacyclononane-l,4,7-tris[methyl(2-carboxyethyl)phosphinic acid) or a derivative thereof; HBED (N,N0-bis(2-hydroxybenzyl)-ethylenediamine-N,N0-diacetic acid) or a derivative thereof; 2,3-HOPO (3-hydroxypyridin-2-one) or a derivative thereof; PCTA(3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-l(15),ll,13-triene-3,6,9,-triacetic acid) or a derivative thereof; DFO (desferri oxamine) or a derivative thereof; DTPA (diethylenetriaminepentaacetic acid) or a derivative thereof; OCTAPA (N,N0-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N, NO-diacetic acid) or a derivative thereof; or H2-MACR0PA (N,N'-bis[(6-carboxy-2-pyridipmethyl]-4,13-diaza-18-crown-6) or a derivative thereof; H2dedpa (1, 2-[[carboxy)-pyri din-2 -yl]-methylamino]ethane or a derivative thereof; and EC20-head comprising P-l-diaminopropionic acid, aspartic acid, and cysteine.

[0133] EE 35. The method of EE 34, wherein the radioisotope is selected from18F,44Sc,47Sc,52Mn,55Co,64Cu,67CU,67Ga,68Ga,86Y,89Zr,90Y, "raTc,inIn,114mIn,117mSn,124I,125I,131I,149Tb,153Sm,152Tb,155Tb,161Tb,177Lu,186Re,188Re,212Pb,212Bi,213Bi,223Ra,224Ra,225Ab,225Ac, and227Th.

[0134] EE 36. The method of any one of EE 23 - EE 35, which further comprises treating the patient with external beam radiation.

[0135] EE 37. The method of any one of EE 23 - EE 36, wherein the cancer is prostate cancer.

Claims

WHAT IS CLAIMED IS:

1. A conjugate of the formula:T-L(Alb)-A(I)in which:T is a ligand that targets prostate-specific membrane antigen (PSMA);A is an inhibitor of poly(ADP-ribose) polymerase (PARP), with the proviso that A is not Inhibitoren, Rucaparib, Olaparib, Niraparib, Veliparib, Iniparib, Pamiparib, EB-47, or Talazoparib;Lis a linker, which links T and A; andAlb is an optional albumin-binding group, in which case L is linked to Alb.

2. The conjugate of claim 1, wherein T is:

3. The conjugate of claim 1, wherein T is:which each of R1and R2is independently selected from hydrogen, carboxylic acid, which is optionally substituted, malonic acid, succinic acid, glutamic acid, and adipic acid.

4. The conjugate of claim 3, wherein the substituted carboxylic acid is thioacetic acid or thiopropionic acid.

5. The conjugate of claim 1, wherein T is a urea of (a) an amino dicarboxylic acid or a derivative thereof and (b) an amino dicarboxylic acid or a derivative thereof, wherein (a) and (b) can be the same or different.

6. The conjugate of claim 1, wherein L comprises a chain of atoms from about 3 atoms to about 30 atoms in length.

7. The conjugate of claim 1, wherein L comprises a chain of atoms from about 5 A to about 45 A in length.

8. The conjugate of claim 1, wherein L comprises a peptide.

9. The conjugate of claim 8, wherein L comprises one or more phenylalanine (Phe) residues, each of which is independently optionally substituted.

10. The conjugate of claim 9, wherein L comprises one or more Phe-Phe, in which at least one Phe is optionally substituted independently of the other Phe.

11. The conjugate of claim 1, wherein L comprises a polyoligoethylene glycol (POEGn), a polyethylene glycol (PEGn), or a combination thereof, wherein n = 1-36.

12. The conjugate of claim 1, wherein L is reductively cleavable.

13. The conjugate of claim 1, wherein L comprises a disulfide.

14. The conjugate of claim 1, wherein L is acid-cleavable.

15. The conjugate of claim 1, wherein L is enzyme-cleavable.

16. The conjugate of claim 1, wherein L is releasable.

17. The conjugate of claim 1, wherein A is XAV-939, PJ34 HC1, AG-14361, A-966492, G007-LK, UPF 1069, AZD2461, 3 -Aminobenzamide, ME0328, NMS-P118, Stenoparib (E7449), NVP-TNKS656, WIKI4, Benzamide, BGP-152HC1, NU1025, Berberine chloride hydrate, JW55, BYK204165, Fluzoparib (SHR-3162), Picolinamide, Nesuparib, Licochalcone D,DR2313. MN 64, 4',5,7-Trimethoxyflavone, M2912, GeA-69, B102(PARP / HDAC-IN-l), Atamparib (RBN-2397), OUL232, Venadaparib (IDX-1197), HI-TOPK-032, 4-Hydroxyquinazoline, RBN012759, Saruparib (AZD5305), AZD9574, or RK-287107.

18. A conjugate having one of the structures:PSMA-Me2-S-S-JnJ19. A conjugate of the formula T-L(AR)-A, in which:T is a ligand that targets prostate-specific membrane antigen (PSMA);L is a linker, which links T and A and T and Anand which is optionally linked to Alb; Alb is an albumin-binding group;AR is a radiotherapeutic or radioimaging agent; andA is an inhibitor of poly(ADP -ribose) polymerase (PARP).

20. The conjugate of claim 19, wherein Alb is an albumin-binding group of the formula:

21. A pharmaceutical composition comprising a conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising a conjugate of claim 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. A method of administering to a patient for a cancer or metastasis thereof, wherein the cancer expresses prostate-specific membrane antigen (PSMA), which method comprises administering to the patient:(i) a conjugate of any one of claims 1-19 or a pharmaceutical composition of claim 21,(ii) a conjugate of claim 20 or a pharmaceutical composition of claim 22, or (iii) simultaneously or sequentially, in either order, (i) and a conjugate of the formula T-L-AR, wherein T is a ligand that targets PSMA, Lis a linker, which links T and AR, and AR is a radiotherapeutic or radioimaging agent,wherein the patient is treated and / or imaged for the cancer or metastasis thereof.

24. The method of claim 23, wherein T in the conjugate of the formula T-L-AR is:

25. The method of claim 23, wherein T is:which each of R1and R2is independently selected from hydrogen, carboxylic acid, which is optionally substituted, malonic acid, succinic acid, glutamic acid, and adipic acid.

26. The method of claim 25, wherein the substituted carboxylic acid is thioacetic acid or thiopropionic acid.

27. The method of claim 23, wherein T in the conjugate of the formula T-L-AR is a urea of (a) an amino dicarboxylic acid or a derivative thereof and (b) an amino dicarboxylic acid or a derivative thereof, wherein (a) and (b) can be the same or different.

28. The method of claim 23, wherein L comprises a chain of atoms from about 3 atoms to about 30 atoms in length.

29. The method of claim 23, wherein L comprises a chain of atoms from about 5 A to about 45 A in length.

30. The method of claim 23, wherein L comprises a peptide.

31. The method of claim 30, wherein L comprises one or more phenylalanine (Phe) residues, each of which is independently optionally substituted.

32. The method of claim 31, wherein L comprises one or more Phe-Phe, in which at least one Phe is optionally substituted independently of the other Phe.

33. The method of claim 23, wherein L comprises a poly oligoethylene glycol (POEGn), a polyethylene glycol (PEGn), or a mixture thereof, wherein n = 1-36.

34. The method of claim 23, wherein AR in the conjugate of the formula T-L-AR comprises a radioisotope bound to a chelator selected from DOTA (1,4,7, 10-tetraazacyclododecane-l, 4, 7,10-tetraacetic acid) or a derivative thereof; TETA(l,4,8,ll-tetraazacyclotetradecane-l,4,8,ll-tetraacetic acid) or a derivative thereof; SarAr (l-N-(4-Aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-l,8-diamine or a derivative thereof; NOTA (1,4,7-triazacyclononane-l,4,7-triacetic acid) or a derivative thereof; NETA (4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[l,4,7]triazonan-l-yl) acetyc acid or a derivative thereof; TRAP (l,4,7-triazacyclononane-l,4,7-tris[methyl(2-carboxyethyl)phosphinic acid) or a derivative thereof; HBED (N,N0-bis(2-hydroxybenzyl)-ethylenediamine-N, NO-diacetic acid) or a derivative thereof; 2,3-HOPO (3-hydroxypyridin-2-one) or a derivative thereof; PCTA (3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-l(15),ll,13-triene-3,6,9,-triacetic acid) or a derivative thereof; DFO (desferri oxamine) or a derivative thereof; DTPA (di ethylenetriaminepentaacetic acid) or a derivative thereof; OCTAPA (N,N0-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N, NO-diacetic acid) or a derivative thereof; or H2-MACROPA (N,N'-bis[(6-carboxy-2-pyridipmethyl]-4,13-diaza-18-crown-6) or a derivative thereof; H2dedpa (l,2-[[carboxy)-pyridin-2-yl]-methylamino]ethane or a derivative thereof; and EC20-head comprising P-l-diaminopropionic acid, aspartic acid, and cysteine.

35. The method of claim 34, wherein the radioisotope is selected from18F,44Sc,47Sc,52Mn,55Co,64Cu,67CU,67Ga,68Ga,86Y,89Zr,90Y, "mTc,niIn,114mIn,117mSn,1241,125I,131I,149Tb,153Sm,152Tb,155Tb,161Tb,177LU,186Re,188Re,212Pb,212Bi,213Bi,223Ra,224Ra,225Ab,225Ac, and227Th.

36. The method of claim 23, which further comprises treating the patient with external beam radiation.

37. The method of claim 23, wherein the cancer is prostate cancer.

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