4FC0

Crystal Structure of Human Kinase Domain of B-raf with a DFG-out Inhibitor

Summary for 4FC0

• Entry DOI: 10.2210/pdb4fc0/pdb
• Related: 3Q96 4DBN
• Descriptor: Serine/threonine-protein kinase B-raf, 2-chloro-3-[(2-cyanopropan-2-yl)oxy]-N-{5-[{2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}(methyl)amino]-2-fluorophenyl}benzamide (3 entities in total)
• Functional Keywords: human serine/theronine protein kinase, kinase drug complex, 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: 65802.85

Authors

Yano, J.K.,Aertgeerts, K. (deposition date: 2012-05-23, release date: 2014-01-08, Last modification date: 2024-02-28)

Primary citation

Hirose, M.,Okaniwa, M.,Miyazaki, T.,Imada, T.,Ohashi, T.,Tanaka, Y.,Arita, T.,Yabuki, M.,Kawamoto, T.,Tsutsumi, S.,Sumita, A.,Takagi, T.,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: 3. Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives.
Bioorg.Med.Chem., 20:5600-5615, 2012

PubMed Abstract: Our aim was to discover RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors that possess strong activity and sufficient oral absorption, and thus, we selected a 5-amino-linked thiazolo[5,4-d]pyrimidine derivative as the lead compound because of its potential kinase inhibitory activities and its desired solubility. The novel tertiary 1-cyano-1-methylethoxy substituent was designed to occupy the hydrophobic region of 'back pocket' of BRAF on the basis of the X-ray co-crystal structure data of BRAF. In addition, we found that N-methylation of the amine linker could control the twisted molecular conformation leading to improved solubility. These approaches produced N-methyl thiazolo[5,4-b]pyridine-5-amine derivative 5. To maximize the in vivo efficacy, we attempted salt formation of 5. Our result indicated that the besylate monohydrate salt form (5c) showed significant improvement of both solubility and oral absorption. Owing to the improved physicochemical properties, compound 5c demonstrated regressive antitumor efficacy in a HT-29 xenograft model.

PubMed: 22883026
DOI: 10.1016/j.bmc.2012.07.032

Experimental method

X-RAY DIFFRACTION (2.95 Å)