KRAS Inhibitor that Simultaneously Inhibits Nucleotide Exchange Activity and Effector Engagement

Authors

Cynthia V Pagba
Amit K Gupta
Ali K Naji
Dharini van der Hoeven
Kelly Churion
Xiaowen Liang
Jacob Jakubec
Magnus Hook
Yan Zuo
Marisela Martinez de Kraatz
Jeffrey A Frost
Alemayehu A Gorfe

Publication Date

12-21-2022

Journal

ACS Bio & Med Chem Au

Abstract

We describe a small molecule ligand ACA-14 (2-hydroxy-5-{[(2-phenylcyclopropyl) carbonyl] amino} benzoic acid) as an initial lead for the development of direct inhibitors of KRAS, a notoriously difficult anticancer drug target. We show that the compound binds to KRAS near the switch regions with affinities in the low micromolar range and exerts different effects on KRAS interactions with binding partners. Specifically, ACA-14 impedes the interaction of KRAS with its effector Raf and reduces both intrinsic and SOS-mediated nucleotide exchange rates. Likely as a result of these effects, ACA-14 inhibits signal transduction through the MAPK pathway in cells expressing mutant KRAS and inhibits the growth of pancreatic and colon cancer cells harboring mutant KRAS. We thus propose compound ACA-14 as a useful initial lead for the development of broad-acting inhibitors that target multiple KRAS mutants and simultaneously deplete the fraction of GTP-loaded KRAS while abrogating the effector-binding ability of the already GTP-loaded fraction.

Keywords

Ras protein, inhibitor, signal transduction, anticancer drug, allosteric inhibition