Small molecule inhibition of a PDZ-domain interaction
View Patent ↗Novel compounds that have been found effective in inhibiting PDZ domain interactions, and particularly interactions of PDZ domains in MAGIs with the oncogenic (tumor suppressor) protein PTEN and interactions between the PDZ domain in the Dishevelled (Dvl) protein and other proteins such as the Frizzled (Fz) protein, have the general formula The invention also includes combinatorial libraries, arrays and methods for screening and studying proteins using such compounds. Compounds of the invention have produced apoptosis in certain cell lines that overexpress the Dishevelled protein (Dvl); inhibiting Wnt signaling.
1. A compound having the formula
in which:
R 0 is selected from the group consisting of C 1 -C 3 alkyl, cyclopropyl, halo, OR 5 and S(O) m R 5 in which m is 0, 1 or 2;
R 1 and R 2 are independently selected from the group consisting of C 2 -C 8 alkenyl, phenylcyclopropyl, phenylpropenyl, R 6 —X 2 —C(R 8 )(R 8 )—R 7 —; and R 6 —X 2 —N(R 8 )—R 7 —;
or R 2 is —(CH 2 ) m′ C 6 H 5 , wherein m′ is 0 or an integer from 1 to 3, or R 2 is C 3 -C 6 cycloalkyl;
R 3 and R 4 are independently hydrogen, methyl or ethyl;
R 5 is methyl or ethyl;
R 6 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, aryl, W, Y, NH 2 , NHCONR 3 R 4 , NHCOOR 3 and NHSO 2 R 9 ;
R 7 is selected from the group consisting of a direct bond, an alkyl group having from 1 to 10 carbon atoms, aryl, —(NH) p (CH 2 CH 2 O) q (NH) p — in which p is 0 or 1 and q is an integer from 1 to 4, and W;
R 8 is selected from the group consisting of H, Y, OH, —NHCONR 3 R 4 ; —NHCOOR 3 ; —NHSO 2 R 9 , (CH 2 ) r CO 2 R 3 , and (CH 2 ) r CO 2 NR 3 R 4 in which r is an integer from 1 to 3;
R 9 is aryl or C 1 -C 6 alkyl;
X 2 is selected from the group consisting of a direct bond, —NH—, —N(CH 3 )—, —NCONR 3 R 4 —, NCOOR 3 —, and NSO 2 R 9 ;
W is a saturated carbocyclic group;
Y is selected from the group consisting of COOH, COOR 3 , CONR 3 R 4 , CONHSO 2 R 5 , hydroxymethyl, —CH 2 COOH, CH 2 CONR 3 R 4 ; and 5-tetrazolyl; and
Z is —CH 2 —, —CH(CH 3 )—, C(CH 3 ) 2 — or —CO—;
and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 in which Y is COGH or COOR 3 .
3. A compound according to claim 1 in which R 0 is a C 1 -C 3 alkyl group.
4. A compound according to claim 3 in which R 0 is methyl.
5. A compound according to claim 1 in which R 1 is optionally substituted phenethyl.
6. A compound according to claim 1 in which R 1 is 2-hydroxyethyl.
7. A compound according to claim 1 in which R 2 is n-butyl, phenyl or n-butyrylamido.
8. A compound according to claim 1 in which R 2 is R 6 —X 2 —C(R 8 )(R 8 )—R 7 or R 6 —X 2 —N(R 8 )—R 7 —, and the group R 6 —X 2 —C(R 8 )(R 8 )—R 7 or R 6 —X 2 —N(R 8 )—R 7 — is selected from C 3 -C 8 alkyl; C 3 -C 6 cycloalkyl; C 3 -C 8 alkenyl; —(CH 2 ) m′ C 6 H 5 where m is 0 or an integer from 1-3; —CH 2 OC 6 H 5 , CH 2 COC 6 H 5 , phenyl(C 2 -C 4 alkenyl), or analogous moieties having substituted phenyl groups; optionally substituted phenylcyclopropyl; —(CH 2 ) s OH, —(CH 2 ) s CONH 2 and (CH 2 ) s COOH where s is an integer from 1 to 3; phenyl; thienyl; and optionally substituted C 3 -C 6 cycloalkyl-(C 1 -C 3 alkyl).
9. A compound according to claim 1 in which R 0 is methyl, R 1 is phenethyl, R 2 is n-butyl, X 1 is —CH, Y is COOH and n is 0.
10. A compound according to claim 1 in which R 0 is methyl, R 1 is 2-hydroxyethyl, R 2 is n-butyl, X 1 is —CH, Y is COOH and n is 0.
11. A compound according to claim 1 in which R 2 is phenethyl or 2-hydroxyethyl.
12. A compound according to claim 1 in which R 1 is C 3 -C 8 alkyl.
13. A compound according to claim 1 in which R 0 is methyl, R 1 is n-pentyl, R 2 is phenethyl, and Y is COOH.
14. A method for inhibiting the functioning of a PDZ domain of a protein comprising contacting the protein with an inhibitory effective amount of a compound according to claim 1 .
15. A method for inhibiting the functioning of a PDZ domain of a protein comprising contacting the protein with an inhibitory effective amount of a compound according to claim 5 .
16. A method for inhibiting the functioning of a PDZ domain of a protein comprising contacting the protein with an inhibitory effective amount of a compound according to claim 6 .
17. A method for inhibiting the functioning of a PDZ domain of a protein comprising contacting the protein with an inhibitory effective amount of a compound according to claim 7 .
18. A method for inhibiting the functioning of a PDZ domain of a protein comprising contacting the protein with an inhibitory effective amount of a compound according to claim 8 .
19. A method for inhibiting the functioning of a PDZ domain of a protein comprising contacting the protein with an inhibitory effective amount of a compound according to claim 9 .
20. A method for inhibiting the functioning of a PDZ domain of a protein comprising contacting the protein with an inhibitory effective amount of a compound according to claim 13 .
21. A method according to claim 14 in which the protein is a MAGI protein.
22. A method for treating cancerous cells or a cancer in a patient, wherein the cancerous cells are, or the cancer is, a lung cancer or mesothelioma, the method comprising contacting the cancerous cells with, or administering to the patient, a therapeutically effective amount of a compound according to claim 1 .
23. A method for treating lung cancer or mesothelioma in a patient comprising administering to the patient a therapeutically effective amount of a compound according to claim 9 .
24. A method for treating lung cancer or mesothelioma in a patient comprising administering to the patient a therapeutically effective amount of a compound according to claim 13 .
25. A compound having the formula
in which:
R 0 is C 1 -C 3 alkyl;
R 1 is C 3 -C 8 alkyl;
R 2 is (CH 2 ) m′ C 6 H 5 , wherein m′ is 0 or an integer from 1 to 3;
R 3 is hydrogen, methyl or ethyl;
Y is selected from the group consisting of COOH and COOR 3 ; and
Z is —CH 2 —, —CH(CH 3 )—, C(CH 3 ) 2 — or —CO—;
and pharmaceutically acceptable salts thereof.