4DBN

Crystal Structure of the Kinase domain of Human B-raf with a [1,3]thiazolo[5,4-b]pyridine derivative

Summary for 4DBN

• Entry DOI: 10.2210/pdb4dbn/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, 2-chloro-3-(1-cyanocyclopropyl)-N-[5-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]benzamide (3 entities in total)
• Functional Keywords: kinase drug complex, ser/thr kinase, atp binding, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): P15056
• Total number of polymer chains: 2
• Total formula weight: 65740.73

Authors

Yano, J.K.,Aertgeerts, K. (deposition date: 2012-01-16, release date: 2012-04-11, Last modification date: 2024-02-28)

Primary citation

Okaniwa, M.,Hirose, M.,Imada, T.,Ohashi, T.,Hayashi, Y.,Miyazaki, T.,Arita, T.,Yabuki, M.,Kakoi, K.,Kato, J.,Takagi, T.,Kawamoto, T.,Yao, S.,Sumita, A.,Tsutsumi, S.,Tottori, T.,Oki, H.,Sang, B.C.,Yano, J.,Aertgeerts, K.,Yoshida, S.,Ishikawa, T.
Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds.
J.Med.Chem., 55:3452-3478, 2012

PubMed 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.

PubMed: 22376051
DOI: 10.1021/jm300126x

Experimental method

X-RAY DIFFRACTION (3.15 Å)