Abstract 620: Development of a dual protein farnesyltransferase -geranylgeranyltransferase-I inhibitor with antitumor activity against human cancer cells

Abstract

Abstract Many low molecular weight GTPases such as Ras, Ral and Rho require posttranslational farnestylation or geranylgeranylation for mediating malignant transformation. This prompted the development of farnesyltransferase (FT) inhibitors (FTI) and geranylgeranyltransferase-I (GGT-1) inhibitors (GGTI) as potential anticancer agents. However, when cancer cells are treated with FTIs, K-Ras becomes geranylgeranylated suggesting that inhibition of both FT and GGT-1 may be required to inhibit tumors harboring K-Ras mutations. Recently our group has developed a series of dual FT and GGT-1 inhibitors based on an ethylenediamine scaffold. Among these dual inhibitors FGTI-2734 was most potent in vitro (FT IC50 = 250±190 nM and GGT-1 IC50 = 520±90 nM). In human cancer cells FGTI-2734 inhibits potently HDJ-2 farnesylation, Rap 1A geranylgeranylation and K-Ras prenylation. Furthermore, FGTI-2734 inhibits the phosphorylation of Erk1/2, Akt and S6K, induces p27 accumulation and inhibits potently tumor cell growth. Finally, FGTI-2734 significantly reduces survivin protein levels, and reduction of survivin levels is associated with induction of apoptosis. Thus, this single molecule with dual FT and GGT-1 inhibitory activities may have distinct advantage over selective FTIs and GGTIs and warrants further advanced pre-clinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 620. doi:10.1158/1538-7445.AM2011-620