title: Discovery and structural analysis of Eph receptor tyrosine kinase inhibitors.
abstract: The Eph family of receptor tyrosine kinases has drawn growing attention due to their role in regulating diverse biological phenomena. However, pharmacological interrogation of Eph kinase function has been hampered by a lack of potent and selective Eph kinase inhibitors. Here we report the discovery of compounds 6 and 9 using a rationally designed kinase-directed library which potently inhibit Eph receptor tyrosine kinases, particularly EphB2 with cellular EC(50)s of 40nM. Crystallographic data of EphA3 and EphA7 in complex with the inhibitors show that they bind to the 'DFG-out' inactive kinase conformation and provide valuable information for structure-based design of second generation inhibitors.
authors: Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney street, Boston, MA 02115, USA.
authors: Yongmun
authors: Y
authors: Choi
authors: Farisa
authors: F
authors: Syeda
authors: John R
authors: JR
authors: Walker
authors: Patrick J
authors: PJ
authors: Finerty
authors: Dominic
authors: D
authors: Cuerrier
authors: Amy
authors: A
authors: Wojciechowski
authors: Qingsong
authors: Q
authors: Liu
authors: Sirano
authors: S
authors: Dhe-Paganon
authors: Nathanael S
authors: NS
authors: Gray
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D009536:Niacinamide / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D010766:Phosphorylation; D036081:Receptors, Eph Family / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C000605793:ALW-II-41-27; D001549:Benzamides; D004791:Enzyme Inhibitors; D009536:Niacinamide; D000255:Adenosine Triphosphate; D036081:Receptors, Eph Family