3vo3 | pdb_00003vo3

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

spinqualitylabelsall models 3vo3, resolution 1.52Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3vo3 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 0KF, EDO Related: 3vhe Gene: KDR, FLK1, VEGFR2 (HUMAN) Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [VGFR2_HUMAN] Defects in KDR are associated with susceptibility to hemangioma capillary infantile (HCI) [MIM:602089]. HCI are benign, highly proliferative lesions involving aberrant localized growth of capillary endothelium. They are the most common tumor of infancy, occurring in up to 10% of all births. Hemangiomas tend to appear shortly after birth and show rapid neonatal growth for up to 12 months characterized by endothelial hypercellularity and increased numbers of mast cells. This phase is followed by slow involution at a rate of about 10% per year and replacement by fibrofatty stroma. Note=Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. Function [VGFR2_HUMAN] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC. Publication Abstract from PubMed 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-methylph enyl]-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%). Discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylph enyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (TAK-593), a highly potent VEGFR2 kinase inhibitor.,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 Bioorg Med Chem. 2013 Apr 15;21(8):2333-45. doi: 10.1016/j.bmc.2013.01.074. Epub , 2013 Feb 13. PMID:23498918 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Vascular Endothelial Growth Factor Receptor

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