Electrophiles and electrophile pro-drugs as RAD51 inhibitors
A method comprising co-administering to a subject having cancer, suspected of having cancer, or at risk of developing cancer: a therapeutically effective amount of at least one compound (a) selected from (a)(i) a nitroalkene fatty acid, (a)(ii) an unsaturated fatty acid having an electron withdrawing group, a leaving group, and a carbon-carbon double bond disposed between the electron withdrawing group and the leaving group, (a)(iii) a thiolated nitro fatty acid, or (a)(iv) a dicarboxylic acid compound containing an electron withdrawing group; and a therapeutically effective amount of at least one anti-neoplastic agent (b), wherein the cancer is a cancer with hereditary etiology of defects in DNA repair genes, a cancer with a high rate of spontaneous genomic instability, a cancer that responds well to DNA damaging agent(s), or a cancer that responds well to a combination of DNA damaging agent(s) with immunotherapy.
1. A method comprising co-administering to a subject having cancer, suspected of having cancer, at risk of developing cancer, or in cancer remission:
a therapeutically effective amount of at least one compound (a) selected from (a)(i) a nitroalkene fatty acid, (a)(ii) an unsaturated fatty acid having an electron withdrawing group, a leaving group, and a carbon-carbon double bond disposed between the electron withdrawing group and the leaving group, (a)(iii) a thiolated nitro fatty acid, or (a)(iv) a dicarboxylic acid compound containing an electron withdrawing group; and
a therapeutically effective amount of at least one anti-neoplastic agent (b),
wherein the cancer is a cancer with etiology of defects in DNA repair genes, a cancer with a high rate of spontaneous genomic instability, a cancer that is treated with DNA damaging agent(s), or a cancer that is treated with a combination of DNA damaging agent(s) with immunotherapy.
2. The method of claim 1 , wherein the cancer is breast cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, brain cancer, or skin cancer.
3. The method of claim 1 , wherein the cancer is triple negative breast cancer.
4. The method of claim 1 , wherein the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, multiple myeloma, or lymphoma.
5. The method of claim 1 , wherein the anti-neoplastic agent is a poly (ADP ribose) polymerase inhibitor.
6. The method of claim 5 , wherein the cancer is triple negative breast cancer and the subject is negative for gBRCAm.
7. The method of claim 5 , wherein the subject is resistant to monotreatment with a poly (ADP ribose) polymerase inhibitor.
8. The method of claim 1 , wherein the anti-neoplastic agent is a DNA-damaging agent or DNA-damaging treatment.
9. The method of claim 1 , wherein the anti-neoplastic agent is doxorubicin, cisplatin, olaparib, rucaparib, niraparib, talazoparib, veliparib, camptothecin, or irradiation treatment.
10. The method of claim 1 , wherein the compound (a) is a RAD51 inhibitor.
11. The method of claim 1 , wherein the compound (a) is the nitroalkene fatty acid.
12. The method of claim 11 , wherein the nitroalkene fatty acid is a compound that includes at least one carbon-carbon double bond and at least one nitro group.
13. The method of claim 11 , wherein the nitroalkene fatty acid is of formula I:
wherein R 1 is hydrogen, C 1 -C 24 alkyl, C 1 -C 24 alkenyl, or C 1 -C 24 alkynyl;
R 2 , R 3 , R 7 , and R 8 are each independently, hydrogen, oxygen, C 1 -C 24 alkyl, NO 2 , OH, or OOH;
R 4 is a terminal COOR 6 group, wherein R 6 is hydrogen, C 1 -C 24 alkyl, or a pharmaceutically acceptable counterion;
R 5 is hydrogen, C 1 -C 24 alkyl, or R 4 and R 5 collectively form ═C(R 9 )(R 10 ), wherein R 9 comprises C 1 -C 24 alkyl, C 1 -C 24 alkenyl, or C 1 -C 24 alkynyl, or wherein R 9 is a terminal COOR 6 group, and
R 10 is hydrogen, NO 2 , OH, or OOH;
n is from 1 to 24; and
wherein the nitroalkene fatty acid includes at least one NO 2 group.
14. The method of claim 13 , wherein R 1 is C 1 -C 24 alkyl.
15. The method of claim 13 , wherein R 2 is hydrogen.
16. The method of claim 13 , wherein one of R 3 or R 8 is NO 2 and the other of R 3 or R 8 is hydrogen.
17. The method of claim 13 , wherein R 4 is —COOH.
18. The method of claim 13 , wherein R 5 is hydrogen.
19. The method of claim 13 , wherein R 7 is hydrogen.
20. The method of claim 13 , wherein R 4 is —COOH; R 5 is methyl; and R 7 is methyl.
21. The method of claim 11 , wherein the nitroalkene fatty acid is 10-nitro-octadec-9-enoic acid.
22. The method of claim 11 , wherein the nitroalkene fatty acid is 9-nitro-octadec-9-enoic acid.
23. The method of claim 11 , wherein the nitroalkene fatty acid is 7-NO 2 -nonadec-7-enoic acid.
24. The method of claim 1 , wherein the compound (a) is the compound (a)(ii) and compound (a)(ii) is:
wherein m and n are, independently, an integer from 1 to 10.
25. The method of claim 1 , wherein the compound (a) is the compound (a)(iii) and compound (a)(iii) is:
wherein x is an integer from 1 to 5, and q, m, p, and t are, independently, an integer from 1 to 10.
26. The method of claim 1 , wherein the compound (a) is the compound (a)(iv) and compound (a)(iv) is:
wherein X is an electron withdrawing group and each m and n are, independently, an integer of 1 to 10, or
wherein X is an electron withdrawing group, each Y and Z is, individually, hydrogen or a C 1 to C 10 alkyl, and each m and n are, independently, an integer of 1 to 10.
27. The method of claim 1 , wherein the compound (a) is:
wherein m is from 1 to 10;
n is from 1 to 10;
the double bond is cis to trans; and
X is an electron withdrawing group selected from —NO 2 , —CN, halide, C x F 2×+1 , wherein x is from 1 to 5, SOR, wherein R is H or C 1 -C 6 alkyl, SO 2 R, wherein R is H or C 1 -C 6 alkyl, or SO 3 R, wherein R is H or C 1 -C 6 alkyl.
28. The method of claim 27 , wherein X is —NO 2 .
29. The method of claim 1 , wherein the compound (a) is:
wherein m is from 1 to 10;
n is from 1 to 10;
the double bond is cis to trans;
Y and Z are each, independently a C 1 to C 10 alkyl, alkenyl or alkynyl;
and X is an electron withdrawing group selected from —NO 2 , —CN, halide, C x F 2×+1 , wherein x is from 1 to 5, SOR, wherein R is H or C 1 -C 6 alkyl, SO 2 R, wherein R is H or C 1 -C 6 alkyl, or SO 3 R, wherein R is H or C 1 -C 6 alkyl.
30. The method of claim 1 , wherein the compound (a) is:
wherein m is from 1 to 10;
n is from 1 to 10;
the double bond is cis to trans;
Y and Z are each, independently a C 1 to C 10 alkyl, alkenyl or alkynyl;
and X is an electron withdrawing group selected from —NO 2 , —CN, halide, C x F 2×+1 , wherein x is from 1 to 5, SOR, wherein R is H or C 1 -C 6 alkyl, SO 2 R, wherein R is H or C 1 -C 6 alkyl, or SO 3 R, wherein R is H or C 1 -C 6 alkyl.
31. The method of claim 29 , wherein m is 2 and n is 2.
32. The method of claim 29 , wherein Y and Z are each, independently, a C 1 to C 6 alkyl.
33. The method of claim 29 , wherein Y and Z are each, independently, methyl or ethyl.
34. The method of claim 29 , wherein X is —NO 2 .
35. The method of claim 1 , wherein the compound (a) is:
36. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound (a) selected from (a)(i) a nitroalkene fatty acid, (a)(ii) an unsaturated fatty acid having an electron withdrawing group, a leaving group, and a carbon-carbon double bond disposed between the electron withdrawing group and the leaving group, (a)(iii) a thiolated nitro fatty acid, or (a)(iv) a dicarboxylic acid compound containing an electron withdrawing group; and a therapeutically effective amount of at least one anti-neoplastic agent (b).
37. The method of claim 2 , wherein the nitroalkene fatty acid is of formula I:
and R 1 is C 1 -C 24 alkyl; R 2 , R 5 and R 7 are each hydrogen; one of R 3 or R 8 is NO 2 and the other of R 3 or R 8 is hydrogen; and R 4 is —COOH.
38. The method of claim 37 , wherein the cancer is triple negative breast cancer.
39. The method of claim 37 , wherein the anti-neoplastic agent is a poly (ADP ribose) polymerase inhibitor.
40. The method of claim 37 , wherein the anti-neoplastic agent is a DNA-damaging agent or DNA-damaging treatment.
41. The method of claim 37 , wherein the anti-neoplastic agent is doxorubicin, cisplatin, olaparib, rucaparib, niraparib, talazoparib, veliparib, camptothecin, or irradiation treatment.
42. The method of claim 38 , wherein the anti-neoplastic agent is doxorubicin, cisplatin, olaparib, rucaparib, niraparib, talazoparib, veliparib, camptothecin, or irradiation treatment.
43. The method of claim 2 , wherein the nitroalkene fatty acid is 7-NO 2 -nonadec-7-enoic acid.
44. The method of claim 43 , wherein the cancer is triple negative breast cancer.
45. The method of claim 43 , wherein the anti-neoplastic agent is a poly (ADP ribose) polymerase inhibitor.
46. The method of claim 43 , wherein the anti-neoplastic agent is a DNA-damaging agent or DNA-damaging treatment.
47. The method of claim 43 , wherein the anti-neoplastic agent is doxorubicin, cisplatin, olaparib, rucaparib, niraparib, talazoparib, veliparib, camptothecin, or irradiation treatment.
48. The method of claim 44 , wherein the anti-neoplastic agent is doxorubicin, cisplatin, olaparib, rucaparib, niraparib, talazoparib, veliparib, camptothecin, or irradiation treatment.
49. The method of claim 43 , wherein the anti-neoplastic agent is doxorubicin, cisplatin, olaparib, rucaparib, niraparib, talazoparib, veliparib, or camptothecin.
50. The method of claim 44 , wherein the anti-neoplastic agent is doxorubicin, cisplatin, olaparib, rucaparib, niraparib, talazoparib, veliparib, or camptothecin.
51. The method of claim 1 , wherein the nitroalkene fatty acid is 8-NO 2 -nonadec-7-enoic acid.
52. The method of claim 2 , wherein the nitroalkene fatty acid is 8-NO 2 -nonadec-7-enoic acid.
53. The method of claim 52 , wherein the anti-neoplastic agent is a poly (ADP ribose) polymerase inhibitor.
54. The method of claim 52 , wherein the anti-neoplastic agent is a DNA-damaging agent or DNA-damaging treatment.
55. The method of claim 52 , wherein the anti-neoplastic agent is doxorubicin, cisplatin, olaparib, rucaparib, niraparib, talazoparib, veliparib, camptothecin, or irradiation treatment.
56. The method of claim 1 , wherein the cancer is a cancer with hereditary etiology of defects in DNA repair genes.
57. The method of claim 37 , wherein the cancer is a cancer with hereditary etiology of defects in DNA repair genes.