Pyrrolo[3,2-b]quinoxaline derivatives as types I1/2 and II Eph tyrosine kinase inhibitors: Structure-based design, synthesis, and in vivo validation

TitlePyrrolo[3,2-b]quinoxaline derivatives as types I1/2 and II Eph tyrosine kinase inhibitors: Structure-based design, synthesis, and in vivo validation
Publication TypeJournal Article
Year of Publication2014
AuthorsUnzue A., Dong J., Lafleur K., Zhao H., Frugier E., Caflisch A., Nevado C.
JournalJournal of Medicinal Chemistry
Volume57
Issue15
Pagination6834-6844
Date Published2014 Aug 14
Type of ArticleResearch Article
ISSN1520-4804
KeywordsAnimals, Antineoplastic Agents, Binding, Competitive, Cell Line, Tumor, Computer Simulation, Crystallography, X-Ray, Drug Design, Drug Screening Assays, Antitumor, Heterografts, Humans, Male, Mice, Inbred ICR, Mice, Nude, Molecular Docking Simulation, Neoplasm Transplantation, Pyrroles, Quinoxalines, Receptor, EphA3, Receptor, EphB4, Structure-Activity Relationship, Thermodynamics
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.

DOI10.1021/jm5009242
pubindex

0189

Alternate JournalJ. Med. Chem.
PubMed ID25076195