molecules of the month


oral pan-RAF Type II kinase inhibitor tool

combo. efficacy in KRAS+ models w/ MEKi

SBDD from literature ligands

ACS Med. Chem. Lett., Apr. 21, 2021

Genentech, South San Francisco, CA

1 min read

The Genentech pan-RAF Type II kinase inhibitor, GNE-9815, is an oral chemical probe and among the most highly kinase-selective inhibitors of RAF reported. Interestingly, it minimally engages the hinge region of the kinase with a weak hydrogen bond acceptor and a polarized C-H···O=C hydrogen bond. Type I BRAF inhibitors targeting BRAFV600E have been successfully used in melanoma, but not in KRAS mutant cancers. In fact, in KRAS mutant tumors, Type I BRAF inhibitor treatment paradoxically activates the MAPK signaling pathway by promoting the formation of RAF dimers. Using Type II pan-RAF tools including GNE-9815, the authors were able to validate the combination of Type II pan-RAF inhibitors with MAPK pathway inhibitors in KRAS mutant tumors. A trial of a Type II RAF inhibitor, belvarafenib (HM95573/GDC-5573) in combination with a MEK…

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