Modulators of GTPases and Their Use

Abstract

The present invention relates to molecules which function as modulators (i.e., inhibitors and agonists) of the Ras-homologous (Rho) family of small GTPases (e.g. Rac, Cdc42 and Rho GTPases) and their use to treat diseases, including cancers (including solid tumors-medulloblastoma, ovarian, breast, head and neck, testicular, prostate among others and hematologic malignancies-B cell lymphoma, where these GTPases are overexpressed or hyperactivated), sporadic and genetic diseases where activation of Rho GTPases plays a pivotal role (Menkes disease, rheumatoid arthritis, atherosclerosis, diabetes (type 1), Huntington's disease and Alzheimer's disease) which are mediated through these proteins. Compounds according to the present invention may also be used as a therapy for the treatment of Entamoeba spp. or Acanthamoeba spp. infections, especially including Entamoeba histolytica.

Description

[0001]The present application claims the benefit of priority from provisional application No. 61 / 397,864, filed Jun. 17, 2010, entitled “Ras-related GTPases as Targets of Non-Steroidal Anti-inflammatory Drugs, which is incorporated by reference in its entirety herein.RELATED APPLICATIONS, CLAIM FOR PRIORITY AND GRANT SUPPORT[0002]This invention was made with government support under grants U54MH074425, U54MH084690, R03MH081231 and P3OCA118100 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention relates to molecules which function as modulators (i.e., inhibitors and agonists) of the Ras-homologous (Rho) family of small GTPases (e.g. Rac, Cdc42 and Rho GTPases) and their use to treat diseases, including cancers (including solid tumors-medulloblastoma, ovarian, breast, head and neck, testicular, prostate among others and hematologic malignancies-B cell lymphoma, where these GTPases are overexp...

AI Technical Summary

Benefits of technology

[0025]Accordingly, the present invention relates to a method for modulating, including inhibiting a GTPase in a patient or subject in need of modulation wherein the GTPase is, in particular, a Rac (e.g. Rac1-3) GTPase or Cdc42, the method comprising administering to said patient or subject an effective amount of a compound as set forth hereinabove. The modulator is preferably an antagonist of GTPase. The present invention also relates to methods for modulating disease and / or conditions which are mediated through GTPases, including treating and / or inhibiting the progression of neurologic and inflammatory diseases dependent on Rho GTPases such as Menkes disease, rheumatoid arthritis, atherosclerosis, diabetes (type I), Huntington's disease and Alzheimer's disease; the growth of cancer, including inhibiting and / or reducing the likelihood of the metastasis of cancer comprising administering to a patient or subject in need thereof an effective amount of at least one compound as otherwise disclosed herein. In the case of cancer, compounds according to the present invention may be coadministered with at least one additional anticancer agent to inhibit the growth of and / or otherwise treat the cancer, including reducing the likelihood of metastasis of the treated cancer.

Problems solved by technology

Although Rac1 and Cdc42 have been recognized as attractive therapeutic targets, specific Rae GTPase inhibitors while effective in culture [16; 17] have not been translated to clinical use and there are no established Cdc42 specific inhibitors.

However, the use of statins to block GTPase membrane association has met with only modest success due to their broad spectrum inhibition of protein prenylation resulting in pleiotropic effects on many GTPases and pathways [18].

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