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

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• 作者：Masanori Okaniwa ; Masaaki Hirose ; Takeo Arita ; Masato Yabuki ; Akito Nakamura ; Terufumi Takagi ; Tomohiro Kawamoto ; Noriko Uchiyama ; Akihiko Sumita ; Shunichirou Tsutsumi ; Tsuneaki Tottori ; Yoshitaka Inui ; Bi-Ching Sang ; Jason Yano ; Kathleen Aertgeerts ; Sei Yoshida ; Tomoyasu Ishikawa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 22, 2013
• 年：2013
• 卷：56
• 期：16
• 页码：6478-6494
• 全文大小：741K
• 年卷期：v.56,no.16(August 22, 2013)
• ISSN：1520-4804

文摘

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.