1123580-75-5Relevant academic research and scientific papers
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
Okaniwa, Masanori,Hirose, Masaaki,Arita, Takeo,Yabuki, Masato,Nakamura, Akito,Takagi, Terufumi,Kawamoto, Tomohiro,Uchiyama, Noriko,Sumita, Akihiko,Tsutsumi, Shunichirou,Tottori, Tsuneaki,Inui, Yoshitaka,Sang, Bi-Ching,Yano, Jason,Aertgeerts, Kathleen,Yoshida, Sei,Ishikawa, Tomoyasu
, p. 6478 - 6494 (2013/09/23)
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 (BRAFV600E) and HMVII (NRASQ61K) xenograft models in rats, 8B demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss.
HETEROCYCLIC COMPOUND AND USE THEREOF
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Page/Page column 76, (2010/06/11)
Disclosed is a heterocyclic compound having a strong Raf inhibitory activity. Specifically disclosed is a compound represented by the formula (I), (II) or (III) below, or a salt thereof. (In the formulae, the symbols are as defined in the description.)
