4P4C

Human EphA3 Kinase domain in complex with quinoxaline derivatives

Summary for 4P4C

• Entry DOI: 10.2210/pdb4p4c/pdb
• Descriptor: EPH receptor A3, 2-amino-1-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]quinoxaline-3-carboxamide (3 entities in total)
• Functional Keywords: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 40791.52

Authors

Dong, J.,Caflisch, A. (deposition date: 2014-03-12, release date: 2014-08-13, Last modification date: 2023-09-27)

Primary citation

Unzue, A.,Dong, J.,Lafleur, K.,Zhao, H.,Frugier, E.,Caflisch, A.,Nevado, C.
Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1/2 and II Eph Tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in Vivo Validation.
J.Med.Chem., 57:6834-6844, 2014

PubMed 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.

PubMed: 25076195
DOI: 10.1021/jm5009242

Experimental method

X-RAY DIFFRACTION (1.599 Å)