PDBsum entry 4p4c

Transferase/transferase inhibitor

PDB id: 4p4c

Contents

Protein chain

266 a.a.

Ligands

25Q

Waters ×274

References listed in PDB file

Key reference

• 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.
• Authors: A.Unzue, J.Dong, K.Lafleur, H.Zhao, E.Frugier, A.Caflisch, C.Nevado.
• Ref.: J Med Chem, 2014, 57, 6834-6844. [DOI no: 10.1021/jm5009242]
• PubMed id: 25076195

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.