American Chemical Society
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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

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posted on 2019-05-06, 00:00 authored by Savithri Ramurthy, Benjamin R. Taft, Robert J. Aversa, Paul A. Barsanti, Matthew T. Burger, Yan Lou, Gisele A. Nishiguchi, Alice Rico, Lina Setti, Aaron Smith, Sharadha Subramanian, Victoriano Tamez, Huw Tanner, Lifeng Wan, Cheng Hu, Brent A. Appleton, Mulugeta Mamo, Laura Tandeske, John E. Tellew, Shenlin Huang, Qin Yue, Apurva Chaudhary, Hung Tian, Raman Iyer, A. Quamrul Hassan, Lesley A. Mathews Griner, Laura R. La Bonte, Vesselina G. Cooke, Anne Van Abbema, Hanne Merritt, Kalyani Gampa, Fei Feng, Jing Yuan, Yuji Mishina, Yingyun Wang, Jacob R. Haling, Sepideh Vaziri, Mohammad Hekmat-Nejad, Valery Polyakov, Richard Zang, Vijay Sethuraman, Payman Amiri, Mallika Singh, William R. Sellers, Emma Lees, Wenlin Shao, Michael P. Dillon, Darrin D. Stuart
Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing 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, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.