6N0Q

BRAF in complex with N-(4-methyl-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)phenyl)-3-(trifluoromethyl)benzamide.

Summary for 6N0Q

• Entry DOI: 10.2210/pdb6n0q/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, N-[4-methyl-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)phenyl]-3-(trifluoromethyl)benzamide (3 entities in total)
• Functional Keywords: raf, braf, craf, craf kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 64678.57

Authors

Mamo, M.,Appleton, B.A. (deposition date: 2018-11-07, release date: 2019-10-23, Last modification date: 2024-03-13)

Primary citation

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.
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.
J.Med.Chem., 63:2013-2027, 2020

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 (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, (RAF709; Nishiguchi, G. A.; et al. , , 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 . Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.

PubMed: 31059256
DOI: 10.1021/acs.jmedchem.9b00161

Experimental method

X-RAY DIFFRACTION (2.04 Å)