Jansen, Hanneke, Jahnke, Wolfgang, Gossert, Alvar, Fang, Zhenhao, Marshall, Christopher B., Nishikawa, Tadateru and Ikura, Mitsuhiko (2018) Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site. Cell chemical biology, 25 (11). 1327-1336.e4. ISSN 2451-9448

Abstract

KRAS is frequently mutated in several of the most lethal types of cancer; however, the KRAS protein has proven a challenging drug target. K-RAS4B must be localized to the plasma membrane by prenylation to activate oncogenic signaling, thus we endeavored to target the protein-membrane interface with small-molecule compounds. While all reported lead compounds have low affinity for KRAS in solution, the potency of Cmpd2 was strongly enhanced when prenylated K-RAS4B is associated with a lipid bilayer. We have elucidated a unique mechanism of action of Cmpd2, which simultaneously engages a shallow pocket on KRAS and associates with the lipid bilayer, thereby stabilizing KRAS in an orientation in which the membrane occludes its effector-binding site, reducing RAF binding and impairing activation of RAF. Furthermore, enrichment of Cmpd2 on the bilayer enhances potency by promoting interaction with KRAS. This insight reveals a novel approach to developing inhibitors of membrane-associated proteins.

Item Type:	Article
Keywords:	Animals Antineoplastic Agents Drug Discovery Enzyme Inhibitors Humans Indoles Lipid Bilayers Models, Molecular Piperidines Proto-Oncogene Proteins p21(ras)
Date Deposited:	07 Aug 2025 00:45
Last Modified:	07 Aug 2025 00:45
URI:	https://oak.novartis.com/id/eprint/33073