Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2020-03, Vol.63 (5), p.2013-2027

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2020

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.