Journal of Medicinal Chemistry p. 2013 - 2027 (2020)
Update date:2022-08-18
Topics:
Ramurthy, Savithri
Taft, Benjamin R.
Aversa, Robert J.
Barsanti, Paul A.
Burger, Matthew T.
Lou, Yan
Nishiguchi, Gisele A.
Rico, Alice
Setti, Lina
Smith, Aaron
Subramanian, Sharadha
Tamez, Victoriano
Tanner, Huw
Wan, Lifeng
Hu, Cheng
Appleton, Brent A.
Mamo, Mulugeta
Tandeske, Laura
Tellew, John E.
Huang, Shenlin
Yue, Qin
Chaudhary, Apurva
Tian, Hung
Iyer, Raman
Hassan, A. Quamrul
Mathews Griner, Lesley A.
La Bonte, Laura R.
Cooke, Vesselina G.
Van Abbema, Anne
Merritt, Hanne
Gampa, Kalyani
Feng, Fei
Yuan, Jing
Mishina, Yuji
Wang, Yingyun
Haling, Jacob R.
Vaziri, Sepideh
Hekmat-Nejad, Mohammad
Polyakov, Valery
Zang, Richard
Sethuraman, Vijay
Amiri, Payman
Singh, Mallika
Sellers, William R.
Lees, Emma
Shao, Wenlin
Dillon, Michael P.
Stuart, Darrin D.
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.
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