Abstract IA04: Targeting RAS for anticancer therapy

Abstract

Abstract RAS is the most frequently activated oncoprotein in human cancer. Mutations in KRAS are prevalent in pancreatic, colon, and lung cancer. Despite the need for anti-RAS therapies, there are no clinically successful targeted therapies for RAS. We will present efforts to characterize KRAS G12C covalent inhibitors and compounds that bind to the KRAS P1 pocket. In addition, the Clark lab (U. of Louisville) has identified novel small molecules that bind and directly inhibit RAS function. Uniquely, the current lead compound binds preferentially to the activated form of RAS. It blocks the interaction of RAS with downstream effectors and suppresses the transforming activity of RAS in soft agar assays. The best compounds give an IC50 of ~500 nM in vitro. The inhibitor is active in vivo and suppresses growth of RAS-driven xenografts in NRG mice. There is no detectable toxicity. We have initiated efforts to solve the structure of these inhibitors in complex with RAS, to characterize the nucleotide dependence as well as inhibition of RAS interactions with regulatory and effector proteins in vitro using X-ray crystallography in combination with NMR, biochemical, and bioactivity assays. Results from these analyses will aid in elucidating the specificity and the mechanism of action needed to optimize the inhibitors and facilitate development into a drug candidate. Citation Format: Sharon Campbell, Leiah Carey, Ajit Prakash, Geoff Clark, Sarah Scarry, Jeff Aube. Targeting RAS for anticancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA04.