4KSQ

Crystal Structure of Human B-raf bound to a DFG-out Inhibitor 5B

Summary for 4KSQ

• Entry DOI: 10.2210/pdb4ksq/pdb
• Related: 3Q96 4DBN 4KSP
• Descriptor: Serine/threonine-protein kinase B-raf, N-{7-cyano-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide (2 entities in total)
• Functional Keywords: human serine/theronine protein kinase, kinase drug complex, 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: 65755.76

Authors

Yano, J.K.,Masanori, O. (deposition date: 2013-05-17, release date: 2013-07-24, Last modification date: 2024-02-28)

Primary citation

Okaniwa, M.,Hirose, M.,Arita, T.,Yabuki, M.,Nakamura, A.,Takagi, T.,Kawamoto, T.,Uchiyama, N.,Sumita, A.,Tsutsumi, S.,Tottori, T.,Inui, Y.,Sang, B.C.,Yano, J.,Aertgeerts, K.,Yoshida, S.,Ishikawa, T.
Discovery of a Selective Kinase Inhibitor (TAK-632) Targeting Pan-RAF Inhibition: Design, Synthesis, and Biological Evaluation of C-7-Substituted 1,3-Benzothiazole Derivatives.
J.Med.Chem., 56:6478-6494, 2013

PubMed Abstract: With the aim of discovering a selective kinase inhibitor targeting pan-RAF kinase inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo[5,4-b]pyridine class RAF/VEGFR2 inhibitor 1 and developed a regioselective cyclization methodology for the C-7-substituted 1,3-benzothiazole scaffold utilizing meta-substituted anilines. Eventually, we selected 7-cyano derivative 8B (TAK-632) as a development candidate and confirmed its binding mode by cocrystal structure with BRAF. Accommodation of the 7-cyano group into the BRAF-selectivity pocket and the 3-(trifluoromethyl)phenyl acetamide moiety into the hydrophobic back pocket of BRAF in the DFG-out conformation contributed to enhanced RAF potency and selectivity vs VEGFR2. Reflecting its potent pan-RAF inhibition and slow off-rate profile, 8B demonstrated significant cellular activity against mutated BRAF or mutated NRAS cancer cell lines. Furthermore, in both A375 (BRAF(V600E)) and HMVII (NRAS(Q61K)) xenograft models in rats, 8B demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss.

PubMed: 23906342
DOI: 10.1021/jm400778d

Experimental method

X-RAY DIFFRACTION (3.3 Å)