Biophysical and Biochemical Characterization of Structurally Diverse Small Molecules Hits for KRAS Inhibition

We describe six compounds as early hits for the development of direct inhibitors of KRAS, an important anticancer drug target. We show that these compounds bind to KRAS with affinities in the low micromolar range and exert different effects on its interactions with binding partners. Some of the compounds exhibit selective binding to the activated form of KRAS and inhibit signal transduction through both the MAPK or the phosphatidylinositide 3-kinase PI3K-protein kinase B (AKT) pathway in cells expressing mutant KRAS. Most inhibit intrinsic and/or SOS-mediated KRAS activation while others inhibit RAS-effector interaction. We propose these compounds as starting points for the development of non-covalent allosteric KRAS inhibitors.PMID:38349283 | DOI:10.1002/cbic.202300827

Source: Chembiochem - February 13, 2024 Category: Biochemistry Authors: Cynthia Pagba Amit K Gupta Kasuni Dilsha Parisa Sadrpour Jacob Jakubec Priyanka Prakash Dharini van der Hoeven Kwang-Jin Cho Scott Gilbertson Alemayehu A Gorfe Source Type: research