Modulators of GTPase and use in relevant treatment
The present invention relates to molecules which function as selective modulators (i.e., inhibitors and agonists, preferably inhibitors) of the Ras-homologous (Rho) family of small GTPases, in particular, Cdc42 GTPase and their use to treat diseases, for example cancers, including metastatic cancer, where Cdc42 GTPase is overexpressed or hyperactivated, genetic and acquired diseases where activation of Cdc42 GTPase plays a pivotal role (e.g., neurodegenerative diseases), rheumatoid arthritis, atherosclerosis, diabetes type I, autosomal polycystic kidney diease, cystic kidney disease, precystic kidney disease and microbial infections. Additionally, compounds according to the present invention may be used to inhibit rejection (graft host response) in transplant patients (pursuant to transplantation), to promote immunosuppression, anti-inflammatory response and to mobilize stem cell (migration) in patients in need, among others.
1. A method of therapeutically treating ovarian cancer which overexpresses Cdc42 GTPase in a human patient in need comprising administering to said patient an effective amount of at least one compound according to the chemical structure:
or a pharmaceutically acceptable salt and/or enantiomer thereof, optionally in combination with at least one additional anticancer agent.
2. The method according to claim 1 wherein said at least one compound is co-administered with at least one additional anticancer agent.
3. The method according to claim 1 wherein said compound is
or a pharmaceutically acceptable salt and/enantiomer thereof.
4. The method according to claim 2 wherein said compound is
or a pharmaceutically acceptable salt and/enantiomer thereof.
5. The method according to claim 1 wherein said compound is
or a pharmaceutically acceptable salt and/or enantiomer thereof.
6. The method according to claim 2 wherein said compound is
or a pharmaceutically acceptable salt and/or enantiomer thereof.
7. The method according to claim 1 wherein said compound is
or a pharmaceutically acceptable salt and/or enantiomer thereof.
8. The method according to claim 2 wherein said compound is
or a pharmaceutically acceptable salt and/or enantiomer thereof.
9. The method according to claim 2 wherein said additional anticancer agent is selected from the group consisting of carboplatin, cisplastin, docetaxel, paclitaxel or a mixture thereof.
10. The method according to claim 6 wherein said additional anticancer agent is selected from the group consisting of carboplatin, cisplastin, docetaxel, paclitaxel or a mixture thereof.
11. The method according to claim 8 wherein said additional anticancer agent is selected from the group consisting of carboplatin, cisplatin, docetaxel, paclitaxel or a mixture thereof.
12. The method according to claim 1 wherein said cancer is metastatic.
13. The method according to claim 1 wherein said cancer is drug resistant.
14. The method according to claim 1 wherein said cancer is recurrent.
15. The method according to claim 2 wherein said cancer is metastatic.
16. The method according to claim 2 wherein said cancer is drug resistant.
17. The method according to claim 2 wherein said cancer is recurrent.
18. The method according to claim 5 wherein said cancer is metastatic.
19. The method according to claim 5 wherein said cancer is drug resistant.
20. The method according to claim 6 wherein said cancer is metastatic.
21. The method according to claim 6 wherein said cancer is drug resistant.
22. The method according to claim 8 wherein said cancer is metastatic.
23. The method according to claim 8 wherein said cancer is drug resistant.
24. The method according to claim 1 wherein said compound is administered to said patient in oral dosage form.
25. The method according to claim 1 wherein said compound is administered to said patient in parenteral dosage form.
26. The method according to claim 2 wherein said compound is administered to said patient in oral dosage form.
27. The method according to claim 2 wherein said compound is administered to said patient in parenteral dosage form.
28. The method according to claim 3 wherein said compound is administered to said patient in parenteral dosage form.
29. The method according to claim 5 wherein said compound is administered to said patient in parenteral dosage form.
30. The method according to claim 6 wherein said compound is administered to said patient in parenteral dosage form.
31. The method according to claim 7 wherein said compound is administered to said patient in parenteral dosage form.
32. The method according to claim 8 wherein said compound is administered to said patient in parenteral dosage form.
33. A method of reducing the likelihood that ovarian cancer which overexpresses Cdc42 GTPase in a human patient will metastasize, the method comprising administering to said patient an effective amount of at least one compound according to the chemical structure:
or a pharmaceutically acceptable salt and/or enantiomer thereof, optionally in combination with at least one additional anti-cancer agent.
34. The method according to claim 33 wherein said compound is
or a pharmaceutically acceptable salt and/or enantiomer thereof.
35. The method according to claim 33 wherein said compound is
or a pharmaceutically acceptable salt and/or enantiomer thereof.