Abstract 2580: Screening of a mixture-based synthetic combinatorial library identifies small molecules that inhibit the ability of GTP to displace mant-GDP from mutant G12D KRas

Abstract

Abstract Although mutant KRas significantly contributes to human oncogenesis and patient tumor resistance to therapy, there are no anticancer drugs directly targeting mt KRas available in clinic. A major effort in our laboratory is to identify novel compounds that bind mt KRas and inhibit potently and selectively KRas-driven malignant transformation. To this end, we have used a mixture-based synthetic combinatorial library (scaffold ranking library) containing over 6 million compounds in a mant-GDP assay to identify chemical scaffolds that inhibit the ability of GTP to displace mant-GDP from mt G12D KRas. Subsequent screening of the positional scanning libraries derived from the hit mixtures led to several individual compound hits with the most potent inhibiting the ability of GTP to displace mant-GDP from mt G12D KRas with IC50 of 61 μM. Current studies are focused on physical characterization of the hits to mt KRas and cellular activities of these hits in mt KRas-dependent and -independent human cancer cell lines. Citation Format: Perry C. Kennedy, Marc C. Guilanotti, Travis LsVoi, Said M. Sebti. Screening of a mixture-based synthetic combinatorial library identifies small molecules that inhibit the ability of GTP to displace mant-GDP from mutant G12D KRas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2580. doi:10.1158/1538-7445.AM2015-2580