Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction.

ABSTRACT: Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of

SUBMITTER: Hillig RC 

PROVIDER: S-EPMC6377443 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature