title: 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.
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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. masanori.okaniwa@takeda.com
authors.forename: Masanori
authors.initials: M
authors.lastname: Okaniwa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hirose
authors.forename: Takeo
authors.initials: T
authors.lastname: Arita
authors.forename: Masato
authors.initials: M
authors.lastname: Yabuki
authors.forename: Akito
authors.initials: A
authors.lastname: Nakamura
authors.forename: Terufumi
authors.initials: T
authors.lastname: Takagi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Noriko
authors.initials: N
authors.lastname: Uchiyama
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sumita
authors.forename: Shunichirou
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Tottori
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Inui
authors.forename: Bi-Ching
authors.initials: BC
authors.lastname: Sang
authors.forename: Jason
authors.initials: J
authors.lastname: Yano
authors.forename: Kathleen
authors.initials: K
authors.lastname: Aertgeerts
authors.forename: Sei
authors.initials: S
authors.lastname: Yoshida
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020349:Surface Plasmon Resonance
chemical_list: D052160:Benzothiazoles; D047428:Protein Kinase Inhibitors; C005465:benzothiazole