4P5Z

Human EphA3 Kinase domain in complex with quinoxaline derivatives

Summary for 4P5Z

• Entry DOI: 10.2210/pdb4p5z/pdb
• Descriptor: Ephrin type-A receptor 3, 2-amino-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-1H-pyrrolo[2,3-b]quinoxaline-3-carboxamide (3 entities in total)
• Functional Keywords: transferase, transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P29320
• Total number of polymer chains: 1
• Total formula weight: 40963.63

Authors

Dong, J.,Caflisch, A. (deposition date: 2014-03-20, release date: 2014-08-13, Last modification date: 2023-12-20)

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-, 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 (2.002 Å)