5VAM

BRAF in Complex with RAF709

Summary for 5VAM

• Entry DOI: 10.2210/pdb5vam/pdb
• Related: 5VAL
• Descriptor: Serine/threonine-protein kinase B-raf, N-{2-methyl-5'-(morpholin-4-yl)-6'-[(oxan-4-yl)oxy][3,3'-bipyridin]-5-yl}-3-(trifluoromethyl)benzamide (3 entities in total)
• Functional Keywords: braf serine/threonine-protein kinase b-raf, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P15056
• Total number of polymer chains: 2
• Total formula weight: 64912.86

Authors

Mamo, M.,Appleton, B.A. (deposition date: 2017-03-27, release date: 2017-06-28, Last modification date: 2024-03-06)

Primary citation

Nishiguchi, G.A.,Rico, A.,Tanner, H.,Aversa, R.J.,Taft, B.R.,Subramanian, S.,Setti, L.,Burger, M.T.,Wan, L.,Tamez, V.,Smith, A.,Lou, Y.,Barsanti, P.A.,Appleton, B.A.,Mamo, M.,Tandeske, L.,Dix, I.,Tellew, J.E.,Huang, S.,Mathews Griner, L.A.,Cooke, V.G.,Van Abbema, A.,Merritt, H.,Ma, S.,Gampa, K.,Feng, F.,Yuan, J.,Wang, Y.,Haling, J.R.,Vaziri, S.,Hekmat-Nejad, M.,Jansen, J.M.,Polyakov, V.,Zang, R.,Sethuraman, V.,Amiri, P.,Singh, M.,Lees, E.,Shao, W.,Stuart, D.D.,Dillon, M.P.,Ramurthy, S.
Design and Discovery of N-(2-Methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers.
J. Med. Chem., 60:4869-4881, 2017

PubMed Abstract: RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.

PubMed: 28557458
DOI: 10.1021/acs.jmedchem.6b01862

Experimental method

X-RAY DIFFRACTION (2.1 Å)