GGTI-2418
Mechanism of Action and Preclinical Development
GGTI-2418 is a synthetic peptidomimetic inhibitor of geranylgeranyltransferase I (GGTase I) that appears to induce apoptosis by downregulating several pivotal oncogenic and tumor survival pathways. GGTase I catalyzes the lipid posttranslational modification which is required for the function of Rho GTPases (frequently found aberrantly activated in human cancer). GGTase I inhibitors block Rho function in cancer cells and induce a G1 phase cell cycle arrest by a mechanism involving induction of the CDK inhibitors p21waf and p27kip, CDK2 and CDK4 inhibition and hypophoshorylation of the tumor suppressor Rb. GGTase I inhibitors also induce apoptosis by a mechanism involving downregulation of the expression of survivin and suppression of the activation of PI3K/Akt.
Clinical Development
Tigris Pharmaceuticals plans to open a Phase I study evaluating the safety of GGTI-2418 in two top Phase I cancer research centers during the first quarter of 2009.
Publications
- Dan HC, Jiang K, Coppola D et al., Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis. Oncogene 2004:23:706-715.
- Sun J, Ohkanda J, Coppola D et al., Geranylgeranyltransferase I Inhibitor GGTI-2154 induces breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice. Cancer Research 2003:63:8922-8929.
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