Combination therapy of PSMA-targeted radiopharmaceuticals and DNA damage response inhibitors

Abstract

A combination therapy involving the administration of a PSMA-targeted radiopharmaceutical and a DNA damage response inhibitor.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests and priority thereunder of USSN 63 / 496,279, filed on 14 April 2023, the content of which is incorporated herein by reference.

[0002] DNA single-strand and double-strand breaks occur due to various reasons, including cellular exposure to exogenous sources of DNA damage factors such as radiopharmaceuticals, or due to gene mutations in pathways involving BRCA, PTEN, and ATR proteins. Such DNA breaks are repaired through multiple pathways, and inhibition of these repair pathways by administration of DNA damage repair inhibitors (DDRi) leads to the accumulation of single-strand and / or double-strand breaks. Since increased DNA damage leads to an increased rate of cell death in cancer cells, DDRi are being investigated as cancer therapies based on this mechanism. Examples of DDRi include PARP inhibitors (PARPi), ATM inhibitors (ATMi), ATR inhibitors (ATRi), and DNA-PK inhibitors (DNA-PKi).

[0003] However, mutations that enable DDRi monotherapy in cancer cells can also be found in non-cancerous somatic cells, potentially leading to undesirable normal tissue damage with these therapies. Furthermore, many DDRi show only moderate efficacy in vivo when used as monotherapy, and their use may be limited to cancer types that are pre-deficient in some aspects of DNA repair capacity (e.g., PARPi for the treatment of BRCA1 / 2-deficient cancer).

[0004] Therefore, improved cancer treatments are needed, particularly those that are more effective without increasing toxicity in patients. [Overview of the project]

[0005] This disclosure encompasses the finding that therapies that specifically target DNA breaks to cancer cells (but not to normal tissues), when combined with the inhibition of DNA damage repair mechanisms, may lead to improved efficacy and better treatments. Radioactive decay can cause direct physical damage (such as single-strand or double-strand DNA breaks) or indirect damage (such as bystander or crossfire effects) to the biomolecules that make up cells. Radiopharmaceuticals are drugs that deliver radioisotopes to cancer cells, thereby providing a mechanism that induces DNA damage with anti-cancer therapeutic effects. This disclosure relates to the treatment or improvement of cancer. 225 The present invention provides Ac radiopharmaceuticals, specifically small molecule-based radiopharmaceuticals labeled with actinium-225 that target prostate-specific membrane antigen (PSMA)-positive tumors, in combination with DDRi.

[0006] More specifically, a method for treating a mammal having cancer that expresses prostate-specific membrane antigen (PSMA), (i) 225 Administering Ac-radiopharmaceuticals to mammals that have previously received or are currently receiving DNA damage response inhibitors (DDRi), (ii) DDRi, 225 Administering to mammals that have received or are currently receiving Ac-radiopharmaceuticals, or (iii) 225 This includes administering Ac-radiopharmaceuticals to mammals and simultaneously administering DDRi to mammals, In each case, 225 Ac-radiopharmaceuticals are chelated with the compound of formula I, or its stereoisomer. 225 Provides a method including Ac: [ka]

[0007] In some embodiments, the method is 225 This includes administering DDRi to mammals that have previously received or are currently receiving Ac-radiopharmaceuticals.

[0008] In some embodiments, the 225 Ac-radiopharmaceutical is chelated with the following structure and contains 225 Ac: [Chemical Formula]

[0009] In some embodiments, the DDRi is a PARP inhibitor. In some embodiments, the PARP inhibitor is a small molecule PARP inhibitor. In certain embodiments, the small molecule PARP inhibitor is selected from the group consisting of nipalib, niraparib, olaparib, saraparib, talazoparib, pamiparib, rucaparib (camsylate), and veliparib, or analogs thereof. In certain embodiments, the small molecule PARP inhibitor is olaparib.

[0010] In some embodiments, the DDRi is an ATR or ATM inhibitor. In some embodiments, the ATR or ATM inhibitor is a small molecule ATR or ATM inhibitor. In certain embodiments, the small molecule ATR or ATM inhibitor is selected from the group consisting of AZ20, AZD0156, AZD1390, AZD6738, BAY-1895344 (also known as elimusertib), EPT-46464, M3541, M4344, M6620 (previously known as VE-922 or VX-970), NU6027, and VE-821, or analogs thereof. In certain embodiments, the small molecule ATR or ATM inhibitor is ADAD1390, BAY-1895344 (also known as elimusertib), or analogs thereof.

[0011] In some embodiments, DDRi is a DNA-protein kinase (DNA-PK) inhibitor, a WEE1 inhibitor, a Chk1 inhibitor, or a Chk2 inhibitor. In certain embodiments, DDRi is a DNA-PK inhibitor selected from the group consisting of AZD7648, KU-0060648, NU7026, NU7441 (KU-57788), PI-103, PIK-75 HCl, PP121, and SF2523, or analogs thereof. In certain embodiments, the DNA-PK inhibitor is ADAD7648 or an analog.

[0012] In some embodiments, the mammal is a human.

[0013] In some embodiments, the 225 Ac-radiopharmaceuticals are administered to the mammals at a dose of less than 1 MBq / kg per kg of body weight.

[0014] In some embodiments, the 225 Ac-radiopharmaceuticals are administered to the mammals at a dose of less than 250 kBq / kg per kg of body weight.

[0015] In some embodiments, the 225 Ac-radiopharmaceuticals are administered to the mammals at a dose of less than 100 kBq / kg per kg of body weight.

[0016] In some embodiments, the 225 Ac-radiopharmaceuticals are administered to the mammals in unit doses of less than 15 MBq.

[0017] In some embodiments, the 225 Ac-radiopharmaceuticals are administered to the mammals in unit doses of less than 10 MBq.

[0018] In some embodiments, the 225 Ac-radiopharmaceuticals are administered to the mammals in unit doses of less than 5 MBq.

[0019] In some embodiments, the cancer is selected from the group consisting of colorectal cancer, pancreatic ductal adenocarcinoma, small cell lung cancer, prostate cancer, breast cancer, meningioma, Ewing's sarcoma, pleural mesothelioma, head and neck cancer, non-small cell lung cancer, gastrointestinal stromal tumor, uterine leiomyoma, and cutaneous T-cell lymphoma.

[0020] In some embodiments, the cancer is colorectal cancer or pancreatic ductal adenocarcinoma.

[0021] In some embodiments, the administration results in a reduction in tumor volume, stabilization of tumor volume, or a decrease in the rate of tumor volume increase.

[0022] In some embodiments, the administration results in a reduction in the incidence of recurrence or metastasis. [Brief explanation of the drawing]

[0023] [Figure 1] This is a schematic diagram showing the drug administration schedule for olaparib (PARP inhibitor) in a PC3-PSMA xenograft model. [Figure 2A] The relative tumor volume and overall survival in the PC3-PSMA xenograft model after olaparib treatment are shown, respectively. [Figure 2B] The relative tumor volume and overall survival in the PC3-PSMA xenograft model after olaparib treatment are shown, respectively. [Figure 2C] The relative tumor volume and overall survival in the PC3-PSMA xenograft model after olaparib treatment are shown, respectively. [Figure 3] This is a schematic diagram showing the drug administration schedule for elimusertib (an ATR inhibitor also known as BAY-1895344) in a PC3-PSMA xenograft model. [Figure 4A] The relative tumor volume and overall survival in a PC3-PSMA xenograft model after treatment with elimicertib (also known as BAY-1895344) are shown, respectively. [Figure 4B]The relative tumor volume and overall survival in a PC3-PSMA xenograft model after treatment with elimicertib (also known as BAY-1895344) are shown, respectively. [Figure 4C] The relative tumor volume and overall survival in a PC3-PSMA xenograft model after treatment with elimicertib (also known as BAY-1895344) are shown, respectively. [Modes for carrying out the invention]

[0024] This disclosure relates to a combination therapy for treating or improving cancer, which involves the use of a specific radiopharmaceutical in combination with a DNA damage response inhibitor. In particular, the radiopharmaceutical targets prostate-specific membrane antigen (PSMA). 225 It is an Ac-chelated small molecule.

[0025] The radiolabeled targeting moiety (also known as a radiopharmaceutical) is designed to deliver a radioactive payload to damage and kill target cells by targeting a protein or receptor (e.g., PSMA) whose expression is increased in a disease state and / or is specific to diseased cells (e.g., tumor cells).

[0026] definition chemical terms As used herein, the term “isomer” means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound. Compounds of formula I are recognized to have one or more chiral centers and therefore may exist as stereoisomers, e.g., diastereomers (e.g., enantiomers (i.e., (+) or (-))). Unless otherwise stated, the chemical structures shown herein include all of the corresponding stereoisomers, i.e., stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereoisomerically pure forms), as well as mixtures of enantiomers and stereoisomers, e.g., racemates. Enantiomer and stereoisomer mixtures of compounds can usually be separated by well-known methods such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0027] As used herein, the term “stereoisomer” refers to all possible different isomers and conformations that a compound (e.g., any compound of any formula described herein) may have, in particular, all possible stereochemical and conformational isomers of the basic molecular structure, all diastereomers, enantiomers and / or conformers. Some compounds may exist as different tautomers, all of which are included within the scope of this disclosure.

[0028] As used herein, the term “diastereomer” refers to stereoisomers that are not mirror images of each other and cannot be superimposed on each other.

[0029] As used herein, the term “enantiomer” means each of the individual optically active forms of the compound having an optical purity or enantiomer excess of at least 80% (i.e., at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98% (determined by standard methods in the art).

[0030] biological terms ATM stands for ataxia-telangiectasia mutated.

[0031] ATR is an abbreviation for ataxia telangiectasia and Rad3-related.

[0032] BRCA is an abbreviation for breast cancer gene.

[0033] Chk1 is an abbreviation for checkpoint kinase 1.

[0034] Chk2 is an abbreviation for checkpoint kinase 2.

[0035] DDR stands for DNA Damage Response.

[0036] DNA is an abbreviation for deoxyribonucleic acid.

[0037] DNA-PK is an abbreviation for DNA-dependent protein kinase.

[0038] NTSR1 is an abbreviation for neurotensin receptor 1.

[0039] PARP is an abbreviation for poly-ADP-ribose polymerase.

[0040] PTEN is an abbreviation for phosphatase and tensin homolog deleted on chromosome 10.

[0041] WEE1 stands for WEE1 G2 checkpoint kinase.

[0042] Other terms As used herein, the terms “about” or “approximately” refer to a variation of ±10% from the stated quantitative value (and the stated quantitative value itself), unless otherwise indicated or inferred from the context. For example, unless otherwise indicated or inferred from the context, a dose of about 100 kBq / kg refers to a dose range of 100 ± 10% kBq / kg, i.e., 90 kBq / kg to 110 kBq / kg (including both ends).

[0043] As used herein, the terms “combinatorial administration,” “combinatorial administration form,” or “simultaneous administration” mean that two or more drugs are administered to a subject simultaneously or within intervals in which the effects of each drug on the patient may overlap. Therefore, the two or more drugs administered in combination do not need to be administered together. In some embodiments, the two or more drugs are administered within 90 days (e.g., 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 day), within 28 days (e.g., 14, 7, 6, 5, 4, 3, 2, or 1 day), within 24 hours (e.g., 12, 6, 5, 4, 3, 2, or 1 hour), or within approximately 60, 30, 15, 10, 5, or 1 minute. In some embodiments, the administration of each drug is carried out at intervals close enough to achieve a combinatorial effect.

[0044] As used herein, “administering” a drug to a subject includes bringing the cells of the subject into contact with the drug.

[0045] The term "cancer" refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas. "Solid tumor cancer" refers to cancers that contain an abnormal mass of tissue, such as sarcomas, carcinomas, and lymphomas. As used interchangeably herein, "blood cancer" or "fluid cancer" refers to cancers that exist in bodily fluids, such as lymphomas and leukemias.

[0046] As used herein, the term "chelate" refers to an organic compound or a portion thereof that can be bonded at two or more points to a central metal or radioactive metal atom.

[0047] As used herein, the term “conjugate” refers to a molecule containing a chelating group or its metal complex, a linker group, and optionally a therapeutic or targeted moiety.

[0048] As used herein, the term “compound” includes all stereoisomers, geometric isomers, and tautomers of the structure shown.

[0049] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted atoms can be isolated in optically active forms or in racemic forms. Methods for preparing optically active forms from optically active starting materials are well known in the art, for example, by the division of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are conceived in this disclosure. Although cis and trans geometric isomers of the compounds of this disclosure are described, they can be isolated as mixtures of isomers or in separated isomer forms.

[0050] The compounds of this disclosure also include tautomerized forms. Tautomerized forms arise from the swapping of single bonds with adjacent double bonds and the resulting transfer of protons. Tautomerized forms include prototropic tautomers, which are protonated states of isomers having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, amide-imoid acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomerized forms may be in equilibrium or sterically fixed to a single form by appropriate substitution.

[0051] Substituents of the compounds of this disclosure are disclosed in groups or ranges in various parts of this specification. This disclosure specifically includes all individual partial combinations of the components of such groups and ranges. For example, "C 1~6 The term “alkyl” is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl elements individually. In this specification, phrases of the form “substitutable X” (e.g., a substituted alkyl) are equivalent to “X (where X is substituted)” (e.g., “alkyl, where alkyl is substituted”). This does not mean that the element “X” (e.g., alkyl) itself is optional.

[0052] As used herein, the terms “decrease,” “decreased,” “increase,” “increase,” or “reduction” and “reduced” (e.g., with respect to treatment outcomes or effects) have meaning relative to a baseline level. In some embodiments, the baseline level is the level determined by the use of the above method with controls in an experimental animal model or clinical trial. In some embodiments, the baseline level is the level in the same subject before treatment or at the start of treatment. In some embodiments, the baseline level is the mean level in a population not treated by the above treatment method.

[0053] As used herein, the term “effective dose” of a drug (e.g., any of the conjugates described above) means an amount sufficient to produce a beneficial or desired outcome, such as a clinical outcome, and therefore “effective dose” depends on the context in which the drug is applied.

[0054] When used in combination with a drug (e.g., a therapeutic agent), the term “lower effective dose” refers to a dose of the drug that is therapeutically effective in the combination therapy described herein and is lower than the dose at which the drug was determined to be therapeutically effective when used as a monotherapy in reference studies or by other therapeutic guidance.

[0055] As used herein, the term “pharmaceutical composition” refers to a composition containing the compounds described herein, formulated with pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is manufactured or marketed with the approval of a government supervisory authority as part of a treatment plan for the treatment of diseases in mammals. The pharmaceutical composition may be formulated, for example, for oral administration in unit dosage forms (e.g., tablets, capsules, caplets, gel caps, or syrups), for topical administration (e.g., as creams, gels, lotions, or ointments), for intravenous administration (e.g., as sterile solutions free of particulate embolic materials and in solvent systems suitable for intravenous use), or as any other formulation described herein.

[0056] As used herein, “pharmaceutically acceptable excipients” means any component other than the compounds described herein (e.g., a solvent capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory to the patient. Examples of excipients include antifouling agents, antioxidants, binders, coatings, compression aids, disintegrants, pigments (colorants), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavoring agents, fragrances, fluidizers (flow enhancers), lubricants, preservatives, printing inks, radiation protectants, adsorbents, suspending agents or dispersants, sweeteners, or water in the form of hydrated compounds. Examples of excipients, though not limited to these, include ascorbic acid, histidine, phosphate buffer, butylated hydroxytoluene (BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0057] As used herein, the term “pharmaceutically acceptable salt” refers to a salt suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, or allergic reactions, within reasonable limits of medical judgment. 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. PH Stahl and CG Wermuth), Wiley-VCH, 2008. Salts may be prepared in situ during the final isolation and purification of the compounds described herein, or they may be prepared separately by reacting the free basic group with a suitable organic acid.

[0058] Compounds may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts containing inorganic or organic acids, or, in the case of the acidic form of the compound, may be prepared from inorganic or organic bases. Often, compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, including hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, or various amines for forming basic salts. Methods for preparing suitable salts are well established in the art.

[0059] Typical acid addition salts include citrate, adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, and 2-hydroxyethanesulfonic acid. Examples of alkali or alkaline earth metal salts include salts, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, toluenesulfons, undecanoates, and valersates. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as, but are not limited to, non-toxic ammonium, quaternary ammonium, and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0060] As used herein, the terms “radiopharmaceutical” or “radioconjugate” refer to any compound or conjugate containing a radioisotope or radionuclide, for example, any of the radioisotopes or radionuclides described herein.

[0061] As used herein, the term “radionic nuclide” refers to an atom capable of undergoing radioactive decay (for example, 3 H, 14 C, 15 N, 18 F, 35 S, 47 Sc, 55 Co,60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 75 Br, 76 Br, 77 Br, 89 Zr, 86 Y, 87 Y, 90 Y, 97 Ru, 99 Tc, 99m Tc, 105 Rh, 109 Pd, 111 In, 123 I, 124 I, 125 I, 131 I, 134 Ce, 149 PM, 149 Tb, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 203 Pb, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, 229 Th, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 117m Sn, 201 Tl). The terms radioactive nuclide, radioisotope, or radioisotope may also be used to describe radioactive nuclides. Radioactive nuclides can be used as detection agents. In some embodiments, the radioactive nuclide is a radionuclide that emits alpha rays. Exemplary radioactive nuclides that can be used in this disclosure include, but are not limited to, 64 Cu, 67 Cu, 68 Ga, 90 Y,149 Tb, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, and 227 Th can be mentioned.

[0062] As used herein and as is well understood in the art, “treating” a condition (e.g., a condition described herein, e.g., cancer) or “treatment” of a condition is an approach to obtain a beneficial or desired outcome, such as a clinical outcome. A beneficial or desired outcome may include, but is not limited to, the reduction or improvement of one or more signs or symptoms, whether detectable or undetectable; a reduction in the severity of a disease, disorder, or symptom; stabilization (i.e., no worsening) of the condition of a disease, disorder, or symptom; prevention of the spread of a disease, disorder, or symptom; delay or slowing of the progression of a disease, disorder, or symptom; improvement or mitigation of a disease, disorder, or symptom; and (partial or complete) remission. In relation to cancer treatment, “improving” may include, for example, a reduction in the incidence of metastasis, a reduction in tumor volume, a reduction in tumor angiogenesis, and / or a reduction in the rate of tumor growth. To “alleviate” a disease, disorder, or symptom means that the severity and / or undesirable clinical symptoms of the disease, disorder, or symptom are reduced and / or the time of progression is slowed or extended compared to the severity or duration of the disease, disorder, or symptom if no treatment is provided.

[0063] DNA damage and repair inhibitors (DDRi) In this disclosure, the terms “DNA damage response inhibitor” and “DNA damage and repair inhibitor” are used interchangeably. In various embodiments, DNA damage and repair inhibitors (DDRi) are administered co-administered with radiopharmaceuticals.

[0064] DNA repair involves multiple molecular pathways that repair single-strand breaks (e.g., the PARP pathway) and double-strand breaks (e.g., BRCA and other genes, e.g., ATR / ATM). PARP inhibition (PARPi) leads to impaired single-strand break repair, which in turn leads to further double-strand breaks. Available PARP inhibitors act through both PARP enzyme inhibition and DNA trapping. Tumor cells with BRCA and / or PTEN mutations are sensitive to PARPi. ATR inhibition (ATRi) leads to impaired double-strand break repair, and the accumulation of double-strand breaks leads to cell death. These inhibitors act by interfering with homologous recombination and non-homologous end joining mechanisms.

[0065] This disclosure relates to a combination therapy of a radiopharmaceutical with a DNA damage and repair inhibitor. This type of combination therapy has been found to bring about unexpected improvements in the treatment of cancer, particularly in cancers that are not expected to respond to DDRi.

[0066] In some embodiments, DDRi is a PARP inhibitor (PARPi). In some embodiments, the PARP inhibitor is selected from the group consisting of niparib, niraparib, olaparib, salparib, pamiparib, rucaparib (cansylate), talazoparib, and veliparib, or analogs thereof. In some embodiments, the PARPi is adavocertib, ADAD2811, or an analog thereof.

[0067] In some embodiments, DDRi is an ATM / ATR inhibitor. In certain embodiments, the ATM / ATR inhibitor is selected from the group consisting of AZ20, AZD0156, AZD1390, AZD6738, BAY-1895344 (also known as elimusertib), EPT-46464, M3541, M4344, M6620 (formerly known as VE-922 or VX-970), NU6027, and VE-821, or analogs thereof. In certain embodiments, the ATM / ATR inhibitor is ADAD1390 or an analog.

[0068] In some embodiments, DDRi is a WEE1 inhibitor, a Chk1 inhibitor, or a Chk2 inhibitor. Examples of WEE1 inhibitors, Chk1 inhibitors, or Chk2 inhibitors include those well known in the art.

[0069] In some embodiments, DDRi is a DNA-dependent protein kinase (DNA-PK) inhibitor. Non-limiting examples of DNA-PK inhibitors include, but are not limited to, AZD7648, KU-0060648, NU7026, NU7441 (KU-57788), PI-103, PIK-75 HCl, PP121, SF2523, and their analogues. In certain embodiments, the DNA-PK inhibitor is ADAD7648 or an analogue thereof.

[0070] subject In some disclosed methods, a therapy (including, for example, a therapeutic agent) is administered to a subject. In some embodiments, the subject is a mammal, such as a human.

[0071] In some embodiments, the subject has previously received or is receiving another therapy. For example, in some embodiments, the subject has previously received or is receiving a radiopharmaceutical. In some embodiments, the subject has previously received or is receiving DDRi.

[0072] In some embodiments, the subject has cancer or is at risk of developing cancer. For example, the subject may have been diagnosed with cancer. The cancer may be primary or metastatic. The subject may have cancer at any stage, e.g., stage I, stage II, stage III, or stage IV, with or without lymph node involvement and with or without metastasis. The provided composition may prevent or reduce further growth of the cancer and / or otherwise improve the cancer (e.g., may prevent or reduce metastasis). In some embodiments, the subject does not have cancer but is determined to be at risk of developing cancer due to one or more risk factors, such as environmental exposure, the presence of one or more gene mutations or variants, or a family history. In some embodiments, the subject has not been diagnosed with cancer.

[0073] In some embodiments, cancer is a solid tumor.

[0074] In some embodiments, solid tumor cancers include breast cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, sarcoma, adrenocortical carcinoma, neuroendocrine carcinoma, Ewing's sarcoma, myeloma, or acute myeloid leukemia.

[0075] In some embodiments, the cancer is a non-solid (e.g., liquid (e.g., blood)) cancer.

[0076] Dosage and Administration Effective dose and lower effective dose This disclosure provides combination therapies in which each therapeutic agent may or may not be therapeutically effective on its own. For example, a method is provided which involves administering a first therapy and a second therapy in amounts that together are effective in treating or improving a disease, such as cancer. In some embodiments, at least one of the first and second therapies is administered to the subject at a lower effective dose. In some embodiments, both the first and second therapies are administered to the subject at lower effective doses.

[0077] In some embodiments, the first therapy comprises a radiopharmaceutical, and the second therapy comprises DDRi.

[0078] In each embodiment, the radiopharmaceutical is chelated with a compound having the following structure. 225 Includes Ac 225 Ac- is a radiopharmaceutical: [ka]

[0079] In some embodiments, the first therapy comprises DDRi, and the second therapy comprises a radiopharmaceutical.

[0080] In some embodiments, the therapeutic combinations disclosed herein are administered to a subject in a form (e.g., dosage and timing) sufficient to cure or at least partially prevent the symptoms of the disease and its complications. In relation to monotherapy ("monotherapy"), the amount appropriate for achieving this objective is defined as the "therapeutic effective dose," i.e., the amount of the compound sufficient to significantly improve at least one symptom associated with the disease or medical condition. The "therapeutic effective dose" generally varies depending on the therapeutic agent. For known therapeutic agents, the relevant therapeutic effective dose is well known to those skilled in the art or can be readily determined by those skilled in the art.

[0081] For example, in the treatment of cancer, a drug or compound that reduces, prevents, delays, suppresses, or blocks any symptom of the disease or condition is therapeutically effective. A therapeutically effective dose of a drug or compound does not need to cure the disease or condition, but by providing treatment for the disease or condition, it delays, interferes with, or prevents the onset of the disease or condition in an individual, or improves the signs of the disease or condition, or alters the duration of the disease or condition, or, for example, reduces the severity or accelerates recovery. For example, a treatment may be therapeutically effective if it causes cancer to regress or slows its growth.

[0082] Effective drug regimens in these uses (e.g., the amount of each therapeutic agent, the relative timing of treatment, etc.) may depend on the severity of the disease or condition, as well as the subject's weight and overall condition. For example, the effective therapeutic dose of a particular composition containing a therapeutic agent applied to a mammal (e.g., a human) can be determined by a person skilled in the art, taking into account individual differences in the mammal's age, weight, and condition. Because certain conjugates in this disclosure have enhanced ability to target and persist cancer cells, the doses of these compounds can be lower than the equivalent dose required for the therapeutic effect of the non-conjugate agent (e.g., about 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% or less). Effective therapeutic doses and / or optimal therapeutic doses can be determined empirically by a person skilled in the art. Therefore, lower effective doses can also be determined by a person skilled in the art.

[0083] Single or multiple doses of a radiopharmaceutical or composition (e.g., a therapeutic agent or a pharmaceutical composition containing a radiopharmaceutical) may be administered at dose levels and patterns selected by the treating physician. Dosage and administration schedules may be determined and adjusted based on the severity of the disease or condition under consideration, which can be monitored throughout the course of treatment, in accordance with methods commonly practiced by clinicians or as described herein.

[0084] In the disclosed combination therapy method, the first and second therapies may be administered to the subject sequentially or simultaneously. For example, a first composition containing the first therapeutic agent and a second composition containing the second therapeutic agent may be administered to the subject sequentially or simultaneously. Alternatively, a composition containing a combination of the first and second therapeutic agents may be administered to the subject.

[0085] In some embodiments, the radiopharmaceutical is administered in a single dose. In some embodiments, the radiopharmaceutical is administered in multiple doses. When the radiopharmaceutical is administered in multiple doses, each dose may be the same or different.

[0086] In some embodiments, DDRi is administered as a single dose. In some embodiments, DDRi is administered multiple times, for example, at least two times, at least three times, etc. In some embodiments, DDRi is administered multiple times according to a regular or semi-regular schedule, for example, once every two weeks, once a week, twice a week, three times a week, or more than three times a week. When DDRi is administered multiple times, the dose of each dose may be the same or different. For example, after administering an initial dose of DDRi, subsequent doses of DDRi may be greater or less than the initial dose.

[0087] In some embodiments, a first dose of DDRi is administered simultaneously with a first dose of the radiopharmaceutical. In some embodiments, a first dose of DDRi is administered before a first dose of the radiopharmaceutical. In some embodiments, a first dose of DDRi is administered after a first dose of the radiopharmaceutical. In some embodiments, a subsequent dose of DDRi is administered.

[0088] In some embodiments, the present disclosure provides a method comprising administering DDRi to a mammal at a dosage of about 1 to 100 mg / kg (e.g., about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, and about 100 mg / kg). In some embodiments, the present disclosure provides a method comprising administering DDRi to a mammal at a dosage of about 5 mg / kg, about 20 mg / kg, about 40 mg / kg, about 50 mg / kg, or about 100 mg / kg.

[0089] In some embodiments, the present disclosure provides a method comprising administering an Ac-radiopharmaceutical to a mammal at a dosage of less than 2 MBq / kg per kg of the mammal's body weight (e.g., less than 1.5 MBq / kg, less than 1 MBq / kg, less than 500 kBq / kg, less than 400 kBq / kg, less than 300 kBq / kg, less than 250 kBq / kg, less than 200 kBq / kg, less than 150 kBq / kg, less than 100 kBq / kg, or less than 50 kBq / kg) 225 Each dosage can be administered to the mammal multiple times.

[0090] In some embodiments, the present disclosure provides a method comprising administering an Ac-radiopharmaceutical to a mammal at a dosage of about 0.1 MBq / kg to about 1.0 MBq / kg per kg of the mammal's body weight (e.g., 0.1 MBq / kg, 0.2 MBq / kg, 0.3 MBq / kg, 0.4 MBq / kg, 0.5 MBq / kg, 0.6 MBq / kg, 0.7 MBq / kg, 0.8 MBq / kg, 0.9 MBq / kg, and 1.0 MBq / kg) 225 In some embodiments, the present disclosure provides a method comprising administering an Ac-radiopharmaceutical to a mammal at a dosage of about 0.5 MBq / kg per the mammal's body weight. 225 In some embodiments, the present disclosure provides a method comprising administering an Ac-radiopharmaceutical to a mammal at a dosage of about 0.5 MBq / kg per the mammal's body weight.

[0091] In some embodiments, the present disclosure provides mammals with a dosage of approximately 1 MBq / kg to approximately 10 MBq / kg per kg of mammalian body weight. 225 The present invention provides a method comprising administering Ac-radiopharmaceuticals. In some embodiments, the present disclosure provides a method to mammals at a dose of approximately 1 MBq / kg to approximately 5 MBq / kg per kg of mammalian body weight. 225 The present invention provides a method comprising administering Ac-radiopharmaceuticals. In some embodiments, the present disclosure provides a method to mammals at a dose of about 1 MBq / kg to about 2 MBq / kg per kg of mammalian body weight. 225 The present invention provides a method comprising administering an Ac-radiopharmaceutical. Each dose can be administered to a mammal once or multiple times. In some embodiments, the present disclosure provides a dose to a mammal at approximately 1 MBq / kg as per 1 kg of the mammal's body weight. 225 The present invention provides a method comprising administering an Ac-radiopharmaceutical. Each dose can be administered to a mammal once or multiple times.

[0092] In some embodiments, 225 Ac-radiopharmaceuticals are administered in doses of less than 250 kBq / kg per kg of body weight in mammals (e.g., approximately 240 kBq / kg, 220 kBq / kg, 200 kBq / kg, 180 kBq / kg, 160 kBq / kg, 150 kBq / kg, 140 kBq / kg, 130 kBq / kg, 120 kBq / kg, 110 kBq / kg, or 100 kBq / kg). Each dose can be administered to mammals multiple times.

[0093] In some embodiments, 225 Ac-radiopharmaceuticals are administered in doses of less than 100 kBq / kg per kg of body weight in mammals (e.g., approximately 90 kBq / kg, 80 kBq / kg, 70 kBq / kg, 60 kBq / kg, 50 kBq / kg, 40 kBq / kg, 30 kBq / kg, 20 kBq / kg, or 10 kBq / kg). Each dose can be administered to mammals multiple times.

[0094] In some embodiments,225 The Ac-radiopharmaceutical is administered to a mammal at a unit dose of less than 15 MBq (e.g., about 14 MBq, about 13 MBq, about 12 MBq, about 11 MBq, about 10 MBq, about 9 MBq, about 8 MBq, about 7 MBq, about 6 MBq, about 5 MBq, about 4 MBq, about 3 MBq, about 2 MBq, about 1 MBq). Each unit dose can be administered to the mammal multiple times.

[0095] In some embodiments, the 225 Ac-radiopharmaceutical is administered to the mammal at a unit dose of less than 10 MBq. Each unit dose can be administered to the mammal multiple times.

[0096] In some embodiments, the 225 Ac-radiopharmaceutical is administered to the mammal at a unit dose of less than 5 MBq. Each unit dose can be administered to the mammal multiple times.

[0097] In some embodiments, the radiopharmaceutical (or its composition) and the DDRi (or its composition) are administered within 28 days of each other (e.g., within 14, 7, 6, 5, 4, 3, 2, or 1 day).

[0098] In some embodiments, the radiopharmaceutical (or its composition) and the DDRi (or its composition) are administered within 90 days of each other (e.g., within 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 day). In various embodiments, the DDRi is administered simultaneously with the radiopharmaceutical. In various embodiments, the DDRi is administered multiple times after the first administration of the radiopharmaceutical.

[0099] In some embodiments, the composition (such as a composition containing a radiopharmaceutical) is administered for radiotherapy planning or diagnostic purposes. When administered for radiotherapy planning or diagnostic purposes, the composition can be administered to the subject in an amount effective for determining a diagnostically effective dose and / or a therapeutically effective dose. In some embodiments, a first dose of the conjugate or a composition of the present disclosure (e.g., a pharmaceutical composition) is administered in an amount effective for radiotherapy planning, after which a combination therapy comprising the conjugate disclosed herein and another therapeutic agent is administered.

[0100] Pharmaceutical compositions containing one or more agents (e.g., radiopharmaceuticals and / or DDRi) can be formulated and used in various drug delivery systems according to the methods and systems disclosed. One or more physiologically acceptable excipients or carriers may be included in the composition for appropriate formulation. Examples of suitable formulations are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17. th See ed., 1985. For a brief overview of drug delivery methods, see, for example, Langer (Science 249:1527-1533, 1990).

[0101] formulation Pharmaceutical compositions can be formulated for various routes of administration, including, but not limited to, parenteral administration, nasal administration, topical administration, oral administration, or topical administration by transdermal means, for prophylactic and / or therapeutic treatment. Pharmaceutical compositions can be administered parenterally (e.g., by intravenous, intramuscular, or subcutaneous injection), orally, or by topical application to the affected area of ​​a vascular or cancerous condition, or by intra-articular injection. Further examples of routes of administration include intravascular, intra-arterial, intratumoral, intraperitoneal, intraventricular, intradural, as well as nasal, intraocular, intrascleral, intraorbital, rectal, topical, or aerosol inhalation. Sustained-release administration by means such as depot injection or erosive implants or elements can also be specifically conceived. Suitable compositions include compositions comprising a drug (e.g., compounds disclosed herein) dissolved or suspended in an acceptable carrier, preferably an aqueous carrier, such as water, buffer water, saline, or PBS, for example, for parenteral administration. The composition may contain, as necessary, pharmaceutically acceptable auxiliary substances such as pH adjusters and buffers, osmotic pressure adjusters, wetting agents, or cleansing agents, in particular, in order to approximate physiological conditions. In some embodiments, the composition is formulated for oral delivery, and for example, the composition may contain inert components such as binders or fillers for formulating unit dosage forms such as tablets or capsules. In some embodiments, the composition is formulated for topical administration, and for example, the composition may contain inert components such as solvents or emulsifiers for formulating creams, ointments, gels, pastes, or eye drops.

[0102] The composition can be sterilized by conventional sterilization methods or by sterile filtration. The aqueous solution can be packaged for immediate use or lyophilized, and the lyophilized formulation is combined with a sterile aqueous carrier prior to administration. The pH of the formulation is typically 3 to 11, more preferably 5 to 9 or 6 to 8, most preferably 6 to 7, for example, 6 to 6.5. In some embodiments, the solid composition may be packaged as a plurality of single-dose units, each containing a fixed amount of the above drug(s) in a sealed package, for example, a tablet or capsule. In some embodiments, the solid composition may also be packaged in a variable-volume container, such as a squeeze tube designed for topical application of a cream or ointment.

[0103] effect In some embodiments, the methods disclosed herein produce a therapeutic effect.

[0104] In some embodiments, the therapeutic effect results in a reduction in tumor volume, stabilization of tumor volume, or a decrease in the rate of tumor volume increase. In some embodiments, the therapeutic effect includes a reduction in the incidence of recurrence or metastasis. In some embodiments, the therapeutic effect includes tumor regression.

[0105] Other drugs In some embodiments, the disclosed method further includes administering an antiproliferative agent, a radiosensitizer, or an immunosuppressant or immunomodulator.

[0106] As used interchangeably herein, “antiplomerate” or “antiplomerate” means any anticancer agent, including the antiproliferative agents listed in Table 1, any of which may be used in combination with radiopharmaceuticals to treat a condition or disease. Antiproliferative agents also include organoplatinum derivatives, naphthoquinone and benzoquinone derivatives, chrysophanic acid, and their anthraquinone derivatives.

[0107] As used interchangeably in this specification, “immunomodulator” or “immunomodulator” means any immunomodulator, including those listed in Table 1, any of which may be used in combination with the radiopharmaceuticals provided herein.

[0108] As used herein, “radiosensitizer” includes any agent that enhances the sensitivity of cancer cells to radiotherapy. Examples of radiosensitizers, but not limited to, include 5-fluorouracil, platinum analogs (e.g., cisplatin, carboplatin, oxaliplatin), gemcitabine, EGFR antagonists (e.g., cetuximab, gefitinib), farnesyltransferase inhibitors, COX-2 inhibitors, bFGF antagonists, and VEGF antagonists.

[0109] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Examples]

[0110] Example 1. Synthesis of a radiopharmaceutical containing the compound of Formula I The compound of formula I is a small molecule antagonist that targets PSMA and lutetium-177( 177 Lu) or Actinium-225 225 Radiopharmaceuticals can be formed by radiolabeling with radionuclides such as Ac). For the synthesis of compounds of formula I, or the corresponding radionuclide-chelated radiopharmaceuticals, please refer to the following literature: Weineisen M, et al. EJNMMI Research, 2014, 4:63; Weineisen M, et al. J Nucl Med 2015, 56:1169-1176; US 11,129,912 B1; Zacherl et al. J Nucl Med 2021, 62: 669-674; and Hooijman E, et al. Pharmaceutics, 2021, 13: 715.

[0111] Example 2. In a PC3-PSMA heterologous transplant model 225 Therapeutic efficacy of combining Ac-compound I with olaparib (PARP inhibitor) therapy Using a mouse model containing PSMA-overexpressing PC3 (PC3-PSMA, prostate cancer) tumor xenografts, 225 An in vivo combination study was conducted using Ac-compound I and olaparib. Each mouse group (n=5 / group) received a dose insufficient to achieve efficacy with monotherapy (1.23 MBq / kg or 1 μCi per 30 g of mouse). 225 The mice were treated by administering Ac-compound I as a single dose (intravenously). Further mice (n=5 / group) were then treated. 225 In combination with Ac-compound I, olaparib (forced oral administration) was administered daily for 28 consecutive days at dose ranges of 25, 50, or 100 mg / kg. Olaparib administration was as follows: 225 The study was initiated on the same day that Ac-compound I was administered (Figure 1). The olaparib monotherapy group and the solvent control group (n=5 / group) were included as controls. Tumor measurements were performed 2-3 times per week, and tumor volume was calculated using the measured values. The study period was 50 days after the first administration of the drug.

[0112] Tumor growth in test animals was observed over time and expressed as relative tumor volume (RTV, the tumor volume on day X divided by the initial tumor volume on day 0) (Figures 2A-2C). Monotherapy with olaparib was shown to be ineffective at all dose levels tested. 1.23 MBq / kg [ 225 The combination of Ac]-compound I and olaparib is, 225 Compared to Ac]-compound I monotherapy, olaparib monotherapy, or a solvent control group, it demonstrated superior tumor growth inhibition at all dose levels tested.

[0113] Example 3. In a PC3-PSMA heterologous transplant model 225 Therapeutic efficacy of combining Ac-compound I with ATR inhibitors (BAY-1895344 or elimsertib) Using a mouse model containing PSMA-overexpressing PC3 (PC3-PSMA, prostate cancer) tumor xenografts, 225 An in vivo combination study was conducted using Ac-compound I and elimsertib. Each mouse group (n=5 / group) received a dose insufficient to achieve efficacy with monotherapy (1.23 MBq / kg or 1 μCi per 30 g of mouse). 225 The mice were treated by administering Ac-compound I as a single dose (intravenously). Further mice (n=5 / group) were then treated. 225 Elimsertib (forced oral administration, twice daily) was administered in combination with Ac-compound I at dose ranges of 5, 20, or 40 mg / kg over four 1-week cycles (3 days of administration followed by 4 days of rest). The administration of elimsertib was as follows: 225 The study was initiated on the same day that Ac-compound I was administered (Figure 3). The elimsertib monotherapy group and the solvent control group (n=5 / group) were included as controls. Tumor measurements were performed 2-3 times per week, and tumor volume was calculated using the measured values. The study period was 61 days after the first administration of the drug.

[0114] Tumor growth was observed over time and expressed as relative tumor volume (RTV, the value obtained by dividing the tumor volume on day X by the initial tumor volume on day 0) (Figures 4A-4C). Elimsertib as monotherapy showed dose-dependent efficacy. Elimsertib and 1.23 MBq / kg at doses of 5, 20, and 40 mg / kg [ 225 Combination therapy with Ac]-compound I is used in combination with elimsertib monotherapy, 225 It showed superior inhibition of tumor growth compared to Ac]-compound I monotherapy or the solvent control group.

[0115] Example 4. Further PSMA model 225 Evaluation of the therapeutic effect of combining Ac-compound I with olaparib (PARP inhibitor) therapy. Similar to the example in Example 2, use another PSMA overexpression tumor model (e.g., a patient-derived xenograft model based on a spontaneously occurring Hi-Myc PSMA model and / or an ST1273 model). 225In vivo combination studies can be conducted using Ac-compound I and olaparib (see, for example, Simons BW et al. PSMA expression in the Hi-Myc model; extended utility of a representative model of prostate adenocarcinoma for biological insight and as a drug discovery tool. Prostate. 2019 May;79(6):678-685 and Thaysen et al. Development of a prostate cancer PDX model radioresistant to PSMA targeted radionuclide therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023;Part 1 (Regular and Invited Abstracts);2023 Apr 14-19;Orlando, FL. Philadelphia (PA): AACR;Cancer Res 2023;83(7_Suppl):Abstract nr 5039.).

[0116] Tumor growth can be monitored in both the monotherapy and combination therapy groups, and the observed inhibition can be compared between the groups.

[0117] Example 5. Further PSMA model 225 Evaluation of the therapeutic effect of combining Ac-compound I with ATR inhibitor (BAY-1895344 or elimsertib) therapy. Similar to the example in Example 3, use another PSMA overexpression tumor model (e.g., a patient-derived xenograft model based on a spontaneously occurring Hi-Myc PSMA model and / or an ST1273 model). 225In vivo combination studies can be conducted using Ac-compound I and elimsertib. (See, for example, Simons BW et al. PSMA expression in the Hi-Myc model; extended utility of a representative model of prostate adenocarcinoma for biological insight and as a drug discovery tool. Prostate. 2019 May;79(6):678-685 and Thaysen et al. Development of a prostate cancer PDX model radioresistant to PSMA targeted radionuclide therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023;Part 1 (Regular and Invited Abstracts);2023 Apr 14-19;Orlando, FL. Philadelphia (PA): AACR;Cancer Res 2023;83(7_Suppl):Abstract nr 5039.)

[0118] Tumor growth can be monitored in both the monotherapy and combination therapy groups, and the observed inhibition can be compared between the groups.

[0119] Other Embodiments Those skilled in the art will be able to recognize or confirm many equivalents to the specific embodiments of the invention described herein without using anything beyond ordinary experimentation. Such equivalents shall be encompassed in the following claims.

Claims

1. A method for treating a mammal having cancer that expresses prostate-specific membrane antigen (PSMA), (i) ２２５ Administering Ac-radiopharmaceuticals to mammals that have previously received or are currently receiving DNA damage response inhibitors (DDRi), (ii) DDRi, ２２５ Administering to a mammal that has been or is currently being administered Ac-radiopharmaceuticals, or (iii) ２２５ This includes administering Ac-radiopharmaceutical to the mammal and simultaneously administering DDRi to the mammal, In each case, the above ２２５ Ac-radiopharmaceuticals are chelated with the compound of formula I, or its stereoisomer. ２２５ The method, including Ac: 【Chemistry 1】

2. ２２５ The method according to claim 1, comprising administering DDRi to a mammal that has been or is currently being administered an Ac-radiopharmaceutical.

3. The aforementioned ２２５ Ac-radiopharmaceuticals are chelated with compounds having the following structure. ２２５ The method according to claim 1 or 2, comprising Ac: 【Chemistry 2】

4. The method according to any one of claims 1 to 3, wherein the DDRi is a PARP inhibitor.

5. The method according to claim 4, wherein the PARP inhibitor is a small molecule PARP inhibitor.

6. The method according to claim 5, wherein the small molecule PARP inhibitor is selected from the group consisting of niparib, niraparib, olaparib, salparib, talazoparib, pamiparib, rucaparib (cansylate), and veliparib.

7. The method according to claim 6, wherein the small molecule PARP inhibitor is olaparib, salparib, or an analog thereof.

8. The method according to any one of claims 1 to 3, wherein the DDRi is an ATR or ATM inhibitor.

9. The method according to claim 8, wherein the ATR or ATM inhibitor is a small molecule ATR or ATM inhibitor.

10. The method according to claim 9, wherein the small molecule ATR or ATM inhibitor is selected from the group consisting of AZ20, AZD0156, AZD1390, AZD6738, BAY-1895344 (also known as elimsertib), EPT-46464, M3541, M4344, M6620 (formerly known as VE-922 or VX-970), NU6027, and VE-821, or analogs thereof.

11. The method according to claim 10, wherein the small molecule ATR or ATM inhibitor is ADAD1390, BAY-1895344 (also known as elimsertib), or an analog thereof.

12. The method according to any one of claims 1 to 3, wherein the DDRi is a DNA-protein kinase (DNA-PK) inhibitor, a WEE1 inhibitor, a Chk1 inhibitor, or a Chk2 inhibitor.

13. The method according to claim 12, wherein the DDRi is a DNA-PK inhibitor selected from the group consisting of AZD7648, KU-0060648, NU7026, NU7441 (KU-57788), PI-103, PIK-75 HCl, PP121, and SF2523, or analogs thereof.

14. The method according to claim 13, wherein the DNA-PK inhibitor is AZD7648 or an analogue thereof.

15. The method according to any one of claims 1 to 14, wherein the mammal is a human.

16. The above-mentioned ２２５ The method according to any one of claims 1 to 15, wherein the Ac-radioactive pharmaceutical is administered at a dose of less than about 2 MBq / kg per kg of the body weight of the mammal.

17. The aforementioned ２２５ The method according to any one of claims 1 to 16, wherein the Ac-radiopharmaceutical is administered at a dose of less than approximately 250 kBq / kg per kg of body weight of the mammal.

18. The aforementioned ２２５ The method according to any one of claims 1 to 17, wherein the Ac-radiopharmaceutical is administered at a dose of less than approximately 100 kBq / kg per kg of body weight of the mammal.

19. The aforementioned ２２５ The method according to any one of claims 1 to 18, wherein the Ac-radiopharmaceutical is administered to the mammal in a unit dose of less than about 15 MBq.

20. The aforementioned ２２５ The method according to any one of claims 1 to 19, wherein the Ac-radiopharmaceutical is administered to the mammal in a unit dose of less than about 10 MBq.

21. The aforementioned ２２５ The method according to any one of claims 1 to 20, wherein the Ac-radiopharmaceutical is administered to the mammal in a unit dose of less than approximately 5 MBq.

22. The method according to any one of claims 1 to 21, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, colorectal cancer, renal cell carcinoma, bladder cancer, embryonal testicular cancer, neuroendocrine carcinoma, and brain tumor.

23. The method according to claim 22, wherein the cancer is prostate cancer or breast cancer.

24. The method according to any one of claims 1 to 23, wherein the administration results in a reduction in tumor volume, stabilization of tumor volume, or a decrease in the rate of increase of tumor volume.

25. The method according to claim 24, wherein the administration results in a reduction in the incidence of recurrence or a reduction in the incidence of metastasis.

26. The aforementioned mammal, ２２５ The method according to any one of claims 1 to 25, wherein a lower effective dose of Ac-radiopharmaceutical is administered, has been administered, or is currently administered.

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