title: Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds.
abstract: To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.
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: Takashi
authors.initials: T
authors.lastname: Imada
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ohashi
authors.forename: Youko
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Tohru
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Takeo
authors.initials: T
authors.lastname: Arita
authors.forename: Masato
authors.initials: M
authors.lastname: Yabuki
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Kakoi
authors.forename: Juran
authors.initials: J
authors.lastname: Kato
authors.forename: Terufumi
authors.initials: T
authors.lastname: Takagi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yao
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: Hideyuki
authors.initials: H
authors.lastname: Oki
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: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C574651:2-chloro-3-(1-cyanocyclopropyl)-N-(5-((2-((cyclopropylcarbonyl)amino)(1,3)thiazolo(5,4-b)pyridin-5-yl)oxy)-2-fluorophenyl)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007093:Imidazoles; D011724:Pyridazines; D013844:Thiazoles; D040301:Vascular Endothelial Growth Factor Receptor-2; D048493:Proto-Oncogene Proteins B-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3