More than 30% of human cancers harbor mutations in the Mitogen Activated Protein Kinase (MAPK) pathway, most prevalent of which are RAS or BRAF mutations. Effective therapies to treat RAS mutant cancers remain an unmet medical need. CRAF has been demonstrated to be the critical mediator of mutant KRAS-driven tumorigenesis, and to play an essential role in mediating pathway reactivation following MEK inhibitor treatment. Therefore, CRAF presents an attractive target for the therapeutic intervention of RAS<sup>mut</sup> tumors. We initiated a drug discovery program to develop small molecule inhibitors of both B- and CRAF kinase activity in RAS<sup>mut</sup> cancer models. Hits were identified through accelerated hit finding. Data mining enabled us not only to quickly understand the issues to be addressed but also helped us to set the project strategy and define the target compound profile. Hypotheses were postulated, tested utilizing X-ray crystal structures and medicinal chemistry principles. Herein, we will describe how emphasis on physical chemical properties and cellular potency led to the discovery of ATP-competitive, potent, selective inhibitor of RAF that is highly efficacious in KRAS mutant driven models.

Discovery of a potent, highly selective, and efficacious RAF kinase inhibitor to treat non-small lung cancers (NSCLC)

251st National Meeting (2016)

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