1123583-09-4Relevant articles and documents
Design and synthesis of novel DFG-Out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds
Okaniwa, Masanori,Hirose, Masaaki,Imada, Takashi,Ohashi, Tomohiro,Hayashi, Youko,Miyazaki, Tohru,Arita, Takeo,Yabuki, Masato,Kakoi, Kazuyo,Kato, Juran,Takagi, Terufumi,Kawamoto, Tomohiro,Yao, Shuhei,Sumita, Akihiko,Tsutsumi, Shunichirou,Tottori, Tsuneaki,Oki, Hideyuki,Sang, Bi-Ching,Yano, Jason,Aertgeerts, Kathleen,Yoshida, Sei,Ishikawa, Tomoyasu
experimental part, p. 3452 - 3478 (2012/06/17)
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.
