Noncovalent inhibitor targeting multiple KRAS mutations in cancer

A noncovalent pan-KRAS inhibitor could help treat KRAS-mutant cancers by trapping all mutants of KRAS, but not NRAS or HRAS, in their inactive GDP-bound forms.

Removal of the covalent warhead from a KRAS G12C inhibitor tool compound developed by Boehringer Ingelheim GmbH yielded a compound that inhibited proliferation of a mouse B cell line expressing either the G12C, G12D or G12V KRAS mutations with an IC50 >1µM, and subsequent structure-guided optimization experiments yielded a derivative with a prolinol substituent and a pyrimidine linker that inhibited proliferation of the three KRAS mutant cell lines with a mean IC50 of 140 nM, and inhibited the KRAS G12C-expressing cells similarly to the covalent inhibitor parent compound and the marketed covalent KRAS G12C inhibitor Lumakras sotorasib. ...