Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds.

ABSTRACT: The RAS gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein-protein interactions. We have refined crystallization conditions for KRAS₁₆₉^Q61H-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein-protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein-protein interaction inhibitors selected using an intracellular antibody fragment (called

SUBMITTER: Cruz-Migoni A 

PROVIDER: S-EPMC6377466 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature