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CN-121985960-A - Treatment of patients with negative P53 gene mutation, positive KRAS gene mutation and positive BRCA mutation

CN121985960ACN 121985960 ACN121985960 ACN 121985960ACN-121985960-A

Abstract

A method of treatment comprising treating a patient with P53 gene mutation-negative and KRAS gene mutation-positive cancer, a patient with P53 gene mutation-negative and BRCA gene mutation-positive cancer, a patient with KRAS gene mutation-positive and BRCA gene mutation-positive cancer, or a patient with cancer satisfying all three conditions of P53 gene mutation-negative, KRAS gene mutation-positive and BRCA gene mutation-positive, with a drug comprising an AKR1C3 enzyme-activated or hypoxia-activated anticancer prodrug compound or a salt, ester, solvate or isotopic isomer thereof, alone or in combination with other drugs.

Inventors

  • DUAN JIANXIN
  • QI TIANYANG
  • MENG FANYING
  • LIU XING
  • WANG YIZHI
  • LI BING
  • WANG CHENG

Assignees

  • 深圳艾欣达伟医药科技有限公司

Dates

Publication Date
20260505
Application Date
20241018
Priority Date
20231018

Claims (9)

  1. A method of treatment using a drug comprising a DNA alkylating agent prodrug compound and salts, esters, solvates, isotopic isomers thereof, alone or in combination, for treating a cancer, tumor patient selected from the group consisting of patients meeting one of the following conditions: p53 gene mutation is negative, and KRAS gene mutation is positive for cancer patients; P53 gene mutation is negative, and BRCA gene mutation is positive for cancer patients; KRAS gene mutation positive, and BRCA gene mutation positive cancer patients; And simultaneously satisfies three conditions of P53 gene mutation negativity, KRAS gene mutation positivity and BRCA gene mutation positivity.
  2. A method of treatment using a DNA alkylating agent prodrug compound comprising AKR1C3 enzyme activation, beta-glucosidase (beta-D-Glucosidase) activation, carboxylesterase (Carboxylesterase) activation, esterase and caspase-3 (ESTERASE AND CASPASE-3) activation, cathepsin B (Cathepsin B) activation, gamma-glutamyl transpeptidase (gamma-Glutamyltranspeptidase) activation, beta-galactosidase (beta-galactosidase) activation, or hypoxia activation, and salts, esters, solvates, isotopic isomers thereof, alone or in combination, for the treatment of cancer, tumor patients selected from patients meeting one of the following conditions: p53 gene mutation is negative, and KRAS gene mutation is positive for cancer patients; P53 gene mutation is negative, and BRCA gene mutation is positive for cancer patients; KRAS gene mutation positive, and BRCA gene mutation positive cancer patients; And simultaneously satisfies three conditions of P53 gene mutation negativity, KRAS gene mutation positivity and BRCA gene mutation positivity.
  3. A method of treatment using a drug comprising a DNA alkylating agent prodrug compound selected from AKR1C3 enzyme activation, β -glucosidase (β -D-Glucosidase) activation, carboxylesterase (Carboxylesterase) activation, esterase and caspase-3 (ESTERASE AND CASPASE-3) activation, cathepsin B (Cathepsin B) activation, γ -glutamyl transpeptidase (γ -Glutamyltranspeptidase) activation, β -galactosidase (β -galactosidase) activation, or hypoxia-activated DNA alkylating agent prodrug compound, alone or in combination with other drugs, to treat a patient with P53 gene mutation negative and BRCA gene mutation positive cancer.
  4. Methods of treatment P53 gene mutation negative and KRAS gene mutation positive cancer patients are treated with a drug comprising an AKR1C3 enzyme-activated anticancer prodrug compound or a salt, ester, solvate, isotopologue thereof, alone or in combination with other drugs.
  5. Methods of treatment KRAS gene mutation positive and BRCA gene mutation positive cancer patients are treated with a drug comprising an AKR1C3 enzyme-activated anticancer prodrug compound or a salt, ester, solvate, isotopologue thereof, alone or in combination with other drugs.
  6. The method of treatment according to claim 1,2 or 3, The DNA alkylating agent prodrug compound is selected from the group consisting of AKR1C3 enzyme activation, beta-glucosidase (beta-D-Glucosidase) activation, carboxylesterase (Carboxylesterase) activation, esterase and caspase-3 (ESTERASE AND CASPASE-3) activation, cathepsin B (Cathepsin B) activation, gamma-glutamyl transpeptidase (gamma-Glutamyltranspeptidase) activation, beta-galactosidase (beta-galactosidase) activation, or hypoxia activated DNA alkylating agent prodrug compound, preferably from AKR1C3 enzyme activation, beta-glucosidase (beta-D-Glucosidase) activation, hypoxia activated DNA alkylating agent prodrug compound, The hypoxia activated DNA alkylating agent prodrug compound is selected from the structural formulas (1) - (3), the AKR1C3 enzyme activated DNA alkylating agent prodrug compound is selected from the structural formulas (4) - (11), and the beta-glucosidase (beta-D-Glucosidase) or beta-galactosidase (beta-galactosidase) activated DNA alkylating agent prodrug compound is selected from the structural formula (15): Wherein R is independently selected from H, -CH 3 、-CH 2 CH 3 、-CF 3 , X is independently selected from Cl, br, msO, ts O and other leaving functional groups; Wherein, the definitions of R 1 、R 2 、R 3 and Cx are described in the claims in patent application PCT/CN2020/114519, publication number WO2021120717A1 (corresponding to Chinese application number 2020800673113, publication number CN 114466853A); wherein ,R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 is defined as described in the claims in patent application PCT/US2016/039092, publication No. WO2016210175A1 (corresponding to chinese application No. 2016800368985, publication No. CN108024974 a); Wherein, X, Y, Z, R, T, A and X 10 are defined as in the claims in patent application PCT/US2016/021581, publication number WO2016145092A1 (corresponding to Chinese application number 2016800150788, publication number CN 107530556A); Wherein, X, Y, Z, R, D, L 1 , A and X 10 are defined as in patent application PCT/US2016/025665, publication number WO2016161342A3 (corresponding to Chinese application number 2016800200132, publication number CN 108136214A); wherein, R 1 、R 2 、R 3 、R 4 、R 5 、R 8 、R 9 、R 10 is defined as the patent application PCT/CN2020/089692, the publication number WO2020228685A9 (corresponding to Chinese application number 2020800358890, publication number CN 113853379A) is described in the claims; Wherein: A is a substituted or unsubstituted C6-C10 aryl, biaryl or substituted biaryl, a 5-15 membered heteroaryl, or-n=cr 1 R 2 , wherein the substituents at the time of substitution are selected from the group consisting of halo, -CN, -NO 2 、–O-(CH 2 )-O-、-CO 2 H and salts thereof 、-OR 100 、-CO 2 R 100 、-CONR 101 R 102 、-NR 101 R 102 、-NR 100 SO 2 R 100 、-SO 2 R 100 、-SO 2 NR 101 R 10 2 、C1-C6 alkyl, C3-C10 heterocyclyl; Wherein R 100 、R 101 and R 102 are each independently hydrogen, C1-C8 alkyl, C6-C12 aryl, or R 101 and R 102 together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring; wherein each alkyl group is substituted with 1-3 halo groups or 1-3C 1-C6 alkyl groups; R 1 and R 2 are each independently phenyl or methyl; X, Y and Z are each independently hydrogen or halo; r is hydrogen or C1-C6 alkyl or halogen substituted alkyl; Wherein Rw is defined as in the claims in patent application PCT/CN2020/120281, publication number WO2021068952A1 (corresponding to China application number 202080071652.8, publication number CN 114555574A); wherein, R 1 、R 2 、R 3 、R 4 and T are defined as patent application PCT/CN2021/118597 and are described in claims in publication number WO2022057838A 1; Wherein A, E, G, X, Y is defined as described in the claims in patent application PCT/NZ2019/050030, publication No. WO2019190331A1 (corresponding to chinese application No. 2019800234236, publication No. CN111918864 a); Wherein the sugar moiety (sugar) is attached to a phosphoramide mustard residue (15-I) or an ifosfamide mustard residue (15-II), R 1 and R 2 , which may be the same or different, are selected from hydrogen, C1-C4 alkyl or C1-C6 haloalkyl, And the sugar moiety (sugar) is any existing isomer or enantiomer form of a monosaccharide, disaccharide or polysaccharide.
  7. The method of treatment according to claim 4 or 5, AKR1C3 enzyme-activated anticancer prodrug compounds include AKR1C3 enzyme-activated DNA alkylating agent prodrug compounds and AKR1C3 enzyme-activated non-DNA alkylating agent prodrug compounds, The AKR1C3 enzyme activated DNA alkylating agent prodrug compound is selected from the structural formulas (4) - (11) and (15), and the AKR1C3 enzyme activated non-DNA alkylating agent prodrug compound is selected from the structural formulas (12) - (14): Structural formulae (4) - (11) are as defined in claim 6, Wherein ,R 1 、R 2 、R 3 、R 4 、G 1 、G 2 、G 3 、G 4 、E、T、Y、Z、m、n、s、t、v、w、 ring A is as defined in the claims in patent application CN202210585771.6, publication No. CN 115403579A; Wherein, R 1 、R 2a 、R 2b 、R 3 、R 4 、R 5 , n and Z are defined as in the claims in patent application PCT/IB2020/057285, publication number WO2021005586A1 (corresponding to Chinese application number CN202080053804.1, publication number CN 114206870A); wherein R w 、X、R 4 、R 10 、R 13 、R 14 is as defined in the claims in patent application PCT/CN2022/098082, publication number WO2022258043A 1.
  8. The method of treatment according to any one of claim 6 or 7, The compound of formula (1) is selected from the following structural compounds: the compound of formula (2) is selected from the following structural compounds: the compound of formula (3) is selected from the following structural compounds: the compound of formula (4) is selected from the following structural compounds: the compound of formula (5) is selected from the following structural compounds: The compounds of the structural formulas (6) and (7) are selected from the following structural compounds: the compound of formula (8) is selected from the following structural compounds: The compound of formula (9) is selected from the following structural compounds: the compound of formula (10) is selected from the following structural compounds: the compound of formula (11) is selected from the following structural compounds: the compound of formula (12) is selected from the following structural compounds: the compound of formula (13) is selected from the following structural compounds: the compound of formula (14) is selected from the following structural compounds: the compound of formula (15) is selected from the following structural compounds:
  9. a method of treatment according to any one of claims 1 to 5, wherein the additional agent comprises an immune checkpoint inhibitor, a CDK inhibitor, an ATR inhibitor, a CHK inhibitor, a WEE1 inhibitor, in combination.

Description

Treatment of patients with negative P53 gene mutation, positive KRAS gene mutation and positive BRCA mutation Technical Field The invention relates to a method for treating tumors and cancers, in particular to an AKR1C3 enzyme activated/hypoxia activated anticancer prodrug compound for treating cancer and tumor patients with specific gene characteristics, belonging to the field of tumor treatment. Background DNA alkylating agent prodrug AST-3424 (WO 2016145092, WO 2017087428) targeting over-expressed aldehyde ketoreductase 1C3 (AKR 1C 3), CAS number 2097713-69-2, has the following structure: Chemical structural formula of AST-3424 AST-3424 (also known as OBI-3424, TH-3424) enters into cancer cells and is activated by AKR1C3 enzyme overexpressed by the cancer cells to release metabolite AST-2660 (also known as AST-2660). AST-3424 has low toxicity to cancer cells, and has pharmacological effects related to AKR1C3 enzyme expression in animal model and in vitro pharmacological experiments, wherein the prodrug AST-3424 metabolizes AST-2660 under the action of AKR1C3 enzyme and NADPH, and the expression level of the enzyme is positively related to the drug effect (Meng F,Li WF,Jung D,et al.A novel selective AKR1C3-activated prodrug AST-3424/OBI-3424exhibits broad anti-tumor activity.Am J Cancer Res.2021;11(7):3645-3659;Evans K,Duan J,Pritchard T,et al.OBI-3424,a Novel AKR1C3-Activated Prodrug,Exhibits Potent Efficacy against Preclinical Models of T-ALL.Clin Cancer Res.2019;25(14):4493-4503.doi:10.1158/1078-0432.CCR-19-0551;WangY,LiuY,Zhou C,et al.An AKR1C3-specific prodrug with potent anti-tumor activities against T-ALL.Leuk Lymphoma.2020;61(7):1660-1668.doi:10.1080/10428194.2020.1728746;He P,Wang C,WangY,et al.A Novel AKR1C3 Specific Prodrug TH3424 With Potent Antitumor Activity in Liver Cancer[retracted in:Clin Pharmacol Ther.2021Jul;110(1):262].Clin Pharmacol Ther.2021,110(1):229-237.doi:10.1002/cpt.2171). Chemical reaction formula for metabolism of AST-3424 into AST-2660 (2660 in the figure) The medicine has been put into phase II clinic in China and the United states (American NCT03592264, castration prostate cancer and liver cancer; american NCT04315324, T-ALL T lymphocyte acute leukemia; chinese CTR20191399, various solid tumors; CTR20201915, T lymphocyte acute leukemia and B lymphocyte acute leukemia) respectively. Disclosure of Invention In the clinical test of stage AST-3424II carried out in China, the applicant finds that the treatment effect of patients with P53 gene mutation or defect-negative cancers is better than that of patients with P53 gene mutation or defect-positive cancers, so that the applicant speculates that patients with P53 gene mutation or defect-negative tumors and cancers treated by AST-3424 have better treatment effects, namely that patients with P53 gene mutation or defect-negative tumors treated by AST-3424 have more obvious clinical benefits. In a further preclinical pharmacodynamic study, the applicant found that the above-described AKR1C3 enzyme-activated anticancer prodrug compound of the AST-3424 like structure and the hypoxia-activated anticancer prodrug compound of the TH-302 like structure have excellent therapeutic effects on BRCA mutated tumors, i.e., relatively speaking, the above-described AKR1C3 enzyme-activated DNA alkylating agent prodrug compound of the AST-3424 like structure and the hypoxia-activated DNA alkylating agent prodrug compound of the TH-302 like structure have better therapeutic effects on tumor models carrying BRCA pathogenic mutations than those of the wild type (without BRCA mutations or with non-pathogenic BRCA mutations) and differ significantly (refer to PCT/CN2023/081542, corresponding to publication No. WO2023174319 A1). In particular, in the clinical trial of AST-3424II conducted in china, patients with BRCA mutations showed a certain advantage in their therapeutic effect over non-mutated patients. In particular, the applicant found in preclinical studies that AKR1C3 enzyme-activated anticancer prodrug compounds AST-3424, AST have a significant inhibitory effect on Kras-G12D/G12C mutated PDX tumor models, cells (cf. PCT/CN2022/120817, corresponding to examples 1-9 in publication No. WO 2023/046060). Thus, the AKR1C3 enzyme activated anticancer prodrug compound with the similar structure or the similar mechanism of the AST-3424 and the hypoxia activated anticancer prodrug compound with the similar structure of the TH-302 can have better treatment effect on patients with negative p53 gene mutation, positive BRCA mutation and positive KRAS mutation. For this purpose, the following cancer treatment methods are proposed. A method of treatment using a drug comprising a DNA alkylating agent prodrug compound and salts, esters, solvates, isotopic isomers thereof, alone or in combination, for treating a cancer, tumor patient selected from the group consisting of patients meeting one of the following conditions: p53 gene mutation is negative, and KRAS ge