3VO3

Crystal Structure of the Kinase domain of Human VEGFR2 with imidazo[1,2-b]pyridazine derivative

Summary for 3VO3

• Entry DOI: 10.2210/pdb3vo3/pdb
• Related: 3VHE
• Descriptor: Vascular endothelial growth factor receptor 2, N-[3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: vegfr2, kinase domain, tyrosin-protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted (Probable). Isoform 3: Secreted: P35968
• Total number of polymer chains: 1
• Total formula weight: 36846.39

Authors

Oki, H.,Okada, K. (deposition date: 2012-01-19, release date: 2013-03-06, Last modification date: 2024-03-20)

Primary citation

Miyamoto, N.,Sakai, N.,Hirayama, T.,Miwa, K.,Oguro, Y.,Oki, H.,Okada, K.,Takagi, T.,Iwata, H.,Awazu, Y.,Yamasaki, S.,Takeuchi, T.,Miki, H.,Hori, A.,Imamura, S.
Discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (TAK-593), a highly potent VEGFR2 kinase inhibitor
Bioorg.Med.Chem., 21:2333-2345, 2013

PubMed Abstract: Vascular endothelial growth factor (VEGF) plays important roles in tumor angiogenesis, and the inhibition of its signaling pathway is considered an effective therapeutic option for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of 2-acylamino-6-phenoxy-imidazo[1,2-b]pyridazine derivatives. Hybridization of two distinct imidazo[1,2-b]pyridazines 1 and 2, followed by optimization led to the discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (23a, TAK-593) as a highly potent VEGF receptor 2 kinase inhibitor with an IC50 value of 0.95 nM. The compound 23a strongly suppressed proliferation of VEGF-stimulated human umbilical vein endothelial cells with an IC50 of 0.30 nM. Kinase selectivity profiling revealed that 23a inhibited platelet-derived growth factor receptor kinases as well as VEGF receptor kinases. Oral administration of 23a at 1 mg/kg bid potently inhibited tumor growth in a mouse xenograft model using human lung adenocarcinoma A549 cells (T/C=8%).

PubMed: 23498918
DOI: 10.1016/j.bmc.2013.01.074

Experimental method

X-RAY DIFFRACTION (1.52 Å)