4bb4 | pdb_00004bb4
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] Publication Abstract from PubMedB-Raf represents an attractive target for anti-cancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-RafV600E kinase activity both in vitro and in vivo. Investigations into the SAR of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-RafV600E in vitro and showed preferential anti-proliferative activity in mutant B-RafV600E cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-RafV600E A375 xenograft in vivo at a well tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in non-mutant B-Raf cell lines in vitro. Discovery and Optimization of a Novel Series of Potent Mutant B-Raf V600E Selective Kinase Inhibitors.,Vasbinder MM, Aquila B, Augustin M, Chen H, Cheung T, Cook D, Drew L, Fauber BP, Glossop S, Grondine M, Hennessy EJ, Johannes J, Lee S, Lyne PD, Mortl M, Omer C, Palakurthi S, Pontz T, Read J, Sha L, Shen M, Steinbacher S, Wang H, Wu A, Ye M J Med Chem. 2013 Feb 11. PMID:23398453[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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