2x9f | pdb_00002x9f
ephB4 kinase domain inhibitor complex
Structural highlights
Function[EPHB4_HUMAN] Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Together with its cognate ligand/functional ligand EFNB2 plays a central role in heart morphogenesis and angiogenesis through regulation of cell adhesion and cell migration. EPHB4-mediated forward signaling controls cellular repulsion and segregation form EFNB2-expressing cells. Plays also a role in postnatal blood vessel remodeling, morphogenesis and permeability and is thus important in the context of tumor angiogenesis.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedStarting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo. Inhibitors of the tyrosine kinase EphB4. Part 3: Identification of non-benzodioxole-based kinase inhibitors.,Bardelle C, Barlaam B, Brooks N, Coleman T, Cross D, Ducray R, Green I, Brempt CL, Olivier A, Read J Bioorg Med Chem Lett. 2010 Sep 15. PMID:20850301[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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