Compound for anti-cancer therapy that acts by targeting GOF mutant P53 and stimulates P73 to restore the P53 pathway signaling

Patent metadata

Field	Value
Publication number	US-10322123-B2
Application number	US-201515514623-A
Country	US
Kind code	B2
Filing date	Sep 29, 2015
Priority date	Sep 29, 2014
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Penn State Res Found

Inventors

• El-Deiry Wafik S
• Zhang Shengliang

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D307/71

  attached in position 5 · CPC title

• A61K31/496 Primary

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title