Compound for anti-cancer therapy that acts by targeting GOF mutant p53 and stimulates p73 to restore the p53 pathway signaling
The invention includes compositions comprising NSC59984 or a derivative or analogue thereof and a pharmaceutically acceptable carrier. The invention further includes methods of treating or preventing cancer in a subject, comprising the step of administering to the subject the compositions contemplated within the invention.
1. A method of treating cancer in a subject, wherein the cancer is associated with a p53 gain of function (GOF) mutation,
further wherein the cancer is selected from the group consisting of carcinomas, sarcomas, lymphomas, leukemia, blastomas, germ cell cancers, breast cancer, lung cancer, pancreatic cancer, stomach cancer, bone cancer, ovarian cancer, prostate cancer, bladder cancer, cervical cancer, colon cancer, skin cancer, gliomas, esophageal cancer, oral cancer, gallbladder cancer, liver cancer, testicular cancer, uterine cancer, thyroid cancer, and throat cancer.
2. The method of claim 1 , wherein the method comprises administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I) or a salt, solvate, or N-oxide thereof:
wherein in formula (I):
ring A is a monocyclic or bicyclic aryl, a monocyclic or bicyclic heteroaryl, or a monocyclic or bicyclic heterocyclyl ring, and wherein the aryl, heteroaryl, or heterocyclyl ring is optionally substituted with 0-5 R 1 groups;
ring B is a monocyclic or bicyclic aryl, a monocyclic or bicyclic heteroaryl, or a monocyclic or bicyclic heterocyclyl ring, and wherein the aryl, heteroaryl, or heterocyclyl ring is optionally substituted with 0-5 R 2 groups;
the bond between carbon 1 and carbon 2 is either a single bond or a double bond;
each occurrence of R 1 and R 2 are independently selected from the group consisting of —C 1 -C 6 alkyl, —C 1 -C 6 fluoroalkyl, —C 1 -C 6 heteroalkyl, F, Cl, Br, I, —CN, —NO 2 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —NHS(═O) 2 R 5 , —C(═O)R 5 , —OC(═O)R 5 , —CO 2 R 5 , —OCO 2 R 5 , —CH(R 5 ) 2 , —N(R 5 ) 2 , —C(═O)N(R 5 ) 2 , —OC(═O)N(R 5 ) 2 , —NHC(═O)NH(R 5 ), —NHC(═O)R 5 , —NHC(═O)OR 5 , —C(OH)(R 5 ) 2 , and —C(NH 2 )(R 5 ) 2 ;
R 3 and R 4 are each independently selected from the group consisting of H or C 1 -C 6 alkyl, wherein the alkyl group is optionally substituted with 0-5 R 1 groups;
each occurrence of R 5 is independently selected from the group consisting of H or C 1 -C 6 alkyl, wherein the alkyl group is optionally substituted;
x is an integer from 0 to 5; and
y is an integer from 0 to 5.
3. The method of claim 2 , wherein ring A is a monocyclic heterocyclyl ring.
4. The method of claim 2 , wherein ring A is piperazinyl.
5. The method of claim 2 , wherein ring A is 4-methyl piperazinyl.
6. The method of claim 2 , wherein ring B is a monocyclic heteroaryl ring.
7. The method of claim 2 , wherein ring B is a 5- or 6-membered heterocyclyl or heteroaryl ring.
8. The method of claim 7 , wherein the heterocyclyl or heteroaryl ring has one heteroatom, wherein the heteroatom is alpha to the linkage between ring B and carbon 2.
9. The method of claim 2 , wherein ring B is furyl.
10. The method of claim 2 , wherein ring B is 5-nitrofuryl.
11. The method of claim 2 , wherein R 3 and R 4 are each hydrogen.
12. The method of claim 2 , wherein ring A has 1 to 2 ring heteroatoms.
13. The method of claim 2 , wherein ring A has 1 to 2 ring nitrogens.
14. The method of claim 2 , wherein at least one of R 2 is an electron withdrawing group.
15. The method of claim 14 , wherein the at least one R 2 is selected from the group consisting of F, Cl, Br, I, —CN, —NO 2 , —C(═O)R 5 , —CO 2 R 5 , —S(═O)R 5 , and —S(═O) 2 R 5 .
16. The method of claim 14 , wherein the at least one R 2 group is beta to the linkage between ring B and carbon 2.
17. The method of claim 2 , wherein the bond between carbon 1 and carbon 2 is a double bond.
18. The method of claim 2 , wherein the compound of formula (I) is (E)-1-(4-methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one (NSC59984)
19. The method of claim 2 , wherein the compound stimulates p73 activity, targets mutant p53 for degradation and exhibits anti-tumor effects in vivo in a p73-dependent manner.
20. The method of claim 2 , wherein the compound exhibits anti-tumor activity against cancers associated with a p53 gain of function (GOF) mutation.
21. The method of claim 2 , further comprising administering another therapy to the subject.
22. The method of claim 21 , wherein the other therapy is selected from the group consisting of radiation therapy, chemotherapy, and a combination thereof.
23. The method of claim 22 , wherein the other therapy is administered to the subject at a lower level compared to the level when administered in the absence of the compound.