Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic

Direct pharmacological inhibition of RAS has proven difficult, and targeting CRAF has been challenging due to the complex nature of RAF signaling downstream of activated RAS, along with the poor kinase selectivity of potential RAF inhibitors. In this study, we introduce 15 (LXH254, Aversa, R.; et al., Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor designed with an emphasis on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al., J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well-tolerated in preclinical models. However, its high human intrinsic clearance hindered further development, prompting the exploration of closely related analogs. Using a structure-based approach, we developed a pyridine series with an alcohol side chain that interacts with the DFG loop, significantly enhancing cell potency. Further optimization reduced human intrinsic clearance and time-dependent inhibition, leading to the discovery of 15. Due to its promising properties, 15 has advanced through toxicology studies and is now being tested in phase 1 clinical trials.