title: Pyrrolo[3,2-b]quinoxaline derivatives as types I1/2 and II Eph tyrosine kinase inhibitors: structure-based design, synthesis, and in vivo validation.
abstract: The X-ray crystal structures of the catalytic domain of the EphA3 tyrosine kinase in complex with two type I inhibitors previously discovered in silico (compounds A and B) were used to design type I1/2 and II inhibitors. Chemical synthesis of about 25 derivatives culminated in the discovery of compounds 11d (type I1/2), 7b, and 7g (both of type II), which have low-nanomolar affinity for Eph kinases in vitro and a good selectivity profile on a panel of 453 human kinases (395 nonmutant). Surface plasmon resonance measurements show a very slow unbinding rate (1/115 min) for inhibitor 7m. Slow dissociation is consistent with a type II binding mode in which the hydrophobic moiety (trifluoromethyl-benzene) of the inhibitor is deeply buried in a cavity originating from the displacement of the Phe side chain of the so-called DFG motif as observed in the crystal structure of compound 7m. The inhibitor 11d displayed good in vivo efficacy in a human breast cancer xenograft.
authors: Department of Chemistry and ‡Department of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors: Andrea
authors: A
authors: Unzue
authors: Jing
authors: J
authors: Dong
authors: Karine
authors: K
authors: Lafleur
authors: Hongtao
authors: H
authors: Zhao
authors: Emilie
authors: E
authors: Frugier
authors: Amedeo
authors: A
authors: Caflisch
authors: Cristina
authors: C
authors: Nevado
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D064593:Heterografts; D006801:Humans; D008297:Male; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009368:Neoplasm Transplantation; D011758:Pyrroles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011810:Quinoxalines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D036121:Receptor, EphA3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D011758:Pyrroles; D011810:Quinoxalines; D036121:Receptor, EphA3; D036224:Receptor, EphB4