The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition

RAF, a core signaling component of the MAPK kinase cascade,
is
often mutated in various cancers, including melanoma, lung, and colorectal
cancers. The approved inhibitors were focused on targeting the BRAFV600E mutation that results in constitutive activation of kinase
signaling through the monomeric protein (Class I). However, these
inhibitors also paradoxically activate kinase signaling of RAF dimers,
resulting in increased MAPK signaling in normal tissues. Recently,
significant attention has turned to targeting RAF alterations that
activate dimeric signaling (class II and III BRAF and NRAS). However,
the discovery of a potent and selective inhibitor with biopharmaceutical
properties suitable to sustain robust target inhibition in the clinical
setting has proven challenging. Herein, we report the discovery of
exarafenib (15), a highly potent and selective inhibitor
that intercepts the RAF protein in the dimer compatible αC-helix-IN
conformation and demonstrates anti-tumor efficacy in preclinical models
with BRAF class I, II, and III and NRAS alterations.