Biophysical and Biochemical Characterization of Structurally Diverse Small Molecule 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. Biophysical and biochemical characterization of six compounds is presented. The target biding and inhibitory profiles described here suggest that these compounds can serves as useful starting points for the development of allosteric, non‐covalent inhibitors of KRAS for cancer therapy.