Inhibitors of ercc1-xpf and methods of using the same

Patent metadata

Field	Value
Publication number	US-2016296556-A1
Application number	US-201415038585-A
Country	US
Kind code	A1
Filing date	Nov 25, 2014
Priority date	Nov 25, 2013
Publication date	Oct 13, 2016
Grant date	—

Abstract

Compositions and methods for inhibiting the DNA repair protein complex, ERCC1-XPF, and methods to enhance clinical responses to anticancer drugs that interact with DNA such as cisplatin, and to overcome drug resistance due to DNA repair mechanisms, are described.

First claim

1 . A method of treating a subject suffering from a cell proliferative disorder, comprising administering to a cell in need thereof an effective amount of:
at least one anti-proliferative agent that kills the cell via interacting with DNA; and at least one inhibitor of a DNA repair enzyme.

2 . The method of claim 1 , wherein the cell over-expresses the DNA repair enzyme ERCC1-XPF.

3 . The method of claim 2 , wherein the anti-proliferative agent comprises a DNA cross-linking compound.

4 . The method of claim 3 , wherein the DNA cross-linking compound comprises a platinum-containing anti-neoplastic compound.

5 . A method of treating a subject suffering from a cell proliferative disorder, comprising administering to a cell in need thereof:
at least one anti-proliferative agent that kills cells by interacting with DNA, and at least one compound of Formula I, or a stereoisomer, optical isomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof:

wherein: X=alkyl, alkenyl, alkynyl, aryl, or heteroaryl; wherein:
alkyl is from 1 to 5 carbons,
alkenyl is from 2 to 6 carbons,
alkynyl is from 2 to 6 carbons,
aryl is from 6 to 12 carbons and includes aralkyl,
heteroaryl is from 5 to 12 atoms and includes heteroalkyl, and wherein for all cases each system may be further substituted with hydroxy or amino groups;
Y═(CH 2 ) n where n=0 to 3, CHCH, CH 2 CHCH, CHCHCH 2 , CC, CH 2 CC, CCCH 2 , O, NH, S, (SO), O(CO), (CO)O, O(CO)O, NH(CO), (CO)NH, NH(CO)NH, O(CO)NH, NH(CO)O, O(SO 2 ), (SO 2 )O, O(SO 2 )O, NH(SO 2 ), (SO 2 )NH, NH(SO 2 )NH, O(HOPO), (HOPO)O, O(HOPO)O, O(HOPO)NH, NH(HOPO)O, or NH(HOPO)NH;
R 1 and R 2 together or independently=H, alkyl, alkenyl, alkynyl, halogen, OH, OR 5 , where R 5 =alkyl, NH 2 , NHR 5 , NR 5 R 5 , or NO 2 ;
R 3 and R 4 together or independently=H providing both are not H, CO 2 H, CO 2 X, SO 3 H, SO 3 X, (HOPO)OH, or (HOPO)OX.

6 . The method of claim 5 , wherein X is an aralkyl group consisting of para-methylphenyl, Y is (SO 2 )O, R 1 is NH 2 , R 2 is H, and R 3 ═R 4 are both SO 3 H.

7 . A compound having Formula I:

wherein: X=alkyl, alkenyl, alkynyl, aryl, or heteroaryl; wherein:
alkyl is from 1 to 5 carbons,
alkenyl is from 2 to 6 carbons,
alkynyl is from 2 to 6 carbons,
aryl is from 6 to 12 carbons and includes aralkyl,
heteroaryl is from 5 to 12 atoms and includes heteroalkyl, and wherein for all cases each system may be further substituted with hydroxy or amino groups;
Y═(CH 2 ) n where n=0 to 3, CHCH, CH 2 CHCH, CHCHCH 2 , CC, CH 2 CC, CCCH 2 , O, NH, S, (SO), O(CO), (CO)O, O(CO)O, NH(CO), (CO)NH, NH(CO)NH, O(CO)NH, NH(CO)O, O(SO 2 ), (SO 2 )O, O(SO 2 )O, NH(SO 2 ), (SO 2 )NH, NH(SO 2 )NH, O(HOPO), (HOPO)O, O(HOPO)O, O(HOPO)NH, NH(HOPO)O, or NH(HOPO)NH;
R 4 and R 2 together or independently=H, alkyl, alkenyl, alkynyl, halogen, OH, OR 5 , where R 5 =alkyl, NH 2 , NHR 5 , NR 5 R 5 , or NO 2 ;
R 3 and R 4 together or independently=H providing both are not H, CO 2 H, CO 2 X, SO 3 H, SO 3 X, (HOPO)OH, or (HOPO)OX; but
excluding the compound wherein X is para-methylphenyl, Y is (SO 2 )O, R 1 is NH 2 , R 2 is H, and R 3 ═R 4 are both SO 3 H.

8 . (canceled)

9 . (canceled)

10 . The method of the claim 5 , wherein the anti-proliferative agent is administered following administration of, prior to, or simultaneously with, the compound of Formula I.

11 . (canceled)

12 . (canceled)

13 . The method of claim 5 , for the treatment of cancerous solid tumors.

14 . The method of claim 5 , for the treatment of refractory tumors.

15 . A pharmaceutical composition for the treatment of cancer which comprises at least one anti-proliferative agent and at least one DNA repair enzyme inhibitor compound of Formula I, or a stereoisomer, optical isomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

16 . The composition of claim 15 , for the treatment of cancerous solid tumors.

17 . The composition of claim 15 , for the treatment of refractory tumors.

18 . (canceled)

19 . (canceled)

20 . A method of treating cancer, metastasis of cancer and/or modulating drug resistance in a cancer subject in need thereof, comprising:
administering to the subject a therapeutically effective amount of a DNA repair enzyme inhibitor compound of Formula I, or a stereoisomer, optical isomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, sufficient for inhibition of the activity of ERCC1-XPF in a cancer cell, thereby treating the cancer, metastasis of cancer and/or modulating drug resistance in the cancer subject.

21 . The composition of claim 15 , comprising:
the at least one anti-proliferative agent, and the at least one inhibitor, in a mole ratio of the anti-proliferative agent to the inhibitor which exhibits a synergistic cytotoxic or cytostatic effect on cancer cells.

22 . The composition of claim 21 , wherein the anti-proliferative agent and the inhibitor are co-encapsulated.

23 . A method to treat cancer in a subject which method comprises administering to a subject in need of such treatment a therapeutically effective amount of the composition of claim 22 .

24 . The method of claim 23 , wherein the subject is a human.

25 . The method of claim 23 , wherein the subject is a non-human mammal.

Assignees

• Univ Toledo

Inventors

• Patrick Stephan M
• Erhardt Paul W
• Trabbic Christopher

Classifications

• C07C309/67

  of an unsaturated carbon skeleton · CPC title

• C07C323/66

  containing sulfur atoms of sulfo, esterified sulfo or halosulfonyl groups, bound to the carbon skeleton · CPC title

• C07C309/73

  to carbon atoms of non-condensed six-membered aromatic rings · CPC title

• A61K31/255

  of sulfoxy acids or sulfur analogues thereof · CPC title

• A61P35/00

  Antineoplastic agents · CPC title