6N0P

Design and Discovery ofN-(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.

Ramurthy, S., Taft, B.R., Aversa, R.J., Barsanti, P.A., Burger, M.T., Lou, Y., Nishiguchi, G.A., Rico, A., Setti, L., Smith, A., Subramanian, S., Tamez, V., Tanner, H., Wan, L., Hu, C., Appleton, B.A., Mamo, M., Tandeske, L., Tellew, J.E., Huang, S., Yue, Q., Chaudhary, A., Tian, H., Iyer, R., Hassan, A.Q., Mathews Griner, L.A., La Bonte, L.R., Cooke, V.G., Van Abbema, A., Merritt, H., Gampa, K., Feng, F., Yuan, J., Mishina, Y., Wang, Y., Haling, J.R., Vaziri, S., Hekmat-Nejad, M., Polyakov, V., Zang, R., Sethuraman, V., Amiri, P., Singh, M., Sellers, W.R., Lees, E., Shao, W., Dillon, M.P., Stuart, D.D.

(2020) J Med Chem 63: 2013-2027

• PubMed: 31059256 Search on PubMed
• DOI: https://doi.org/10.1021/acs.jmedchem.9b00161
• Primary Citation of Related Structures:  
  6N0P, 6N0Q


• PubMed Abstract: 
  

  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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Organizational Affiliation: 

Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, California 94608, United States.