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 analog 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 colon cancer in a subject comprising 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 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,
wherein the colon cancer is associated with a p53 gain of function (GOF) mutation.
2. The method of claim 1 , wherein ring A is a monocyclic heterocyclyl ring.
3. The method of claim 1 , wherein ring A is piperazinyl.
4. The method of claim 1 , wherein ring A is 4-methyl piperazinyl.
5. The method of claim 1 , wherein ring B is a monocyclic heteroaryl ring.
6. The method of claim 1 , wherein ring B is a 5- or 6-membered heterocyclyl or heteroaryl ring.
7. The method of claim 6 , wherein the heterocyclyl or heteroaryl ring has one heteroatom, wherein the heteroatom is alpha to the linkage between ring B and carbon 2.
8. The method of claim 1 , wherein ring B is furyl.
9. The method of claim 1 , wherein ring B is 5-nitrofuryl.
10. The method of claim 1 , wherein R 3 and R 4 are each hydrogen.
11. The method of claim 1 , wherein ring A has 1 to 2 ring heteroatoms.
12. The method of claim 1 , wherein at least one of 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 .
13. The method of claim 1 , wherein the bond between carbon 1 and carbon 2 is a double bond.
14. The method of claim 1 , wherein the compound of formula (I) is (E)-1-(4-methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one (NSC59984)
15. The method of claim 1 , further comprising administering another therapy to the subject.
16. The method of claim 15 , wherein the other therapy is selected from the group consisting of radiation therapy, chemotherapy, and a combination thereof.
17. The method of claim 16 , 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.