PDBsum entry 4p4c

Transferase/transferase inhibitor

PDB id: 4p4c

Contents

Protein chain

266 a.a.

Ligands

25Q

Waters ×274

PDB id:

4p4c

Name:

Transferase/transferase inhibitor

Title:

Human epha3 kinase domain in complex with quinoxaline derivatives

Structure:

Eph receptor a3. Chain: a. Fragment: kinase domain. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: epha3. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.60Å R-factor: 0.179 R-free: 0.202

Authors:

J.Dong,A.Caflisch

Key ref:

A.Unzue et al. (2014). 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. PubMed id: 25076195 DOI: 10.1021/jm5009242

Date:

12-Mar-14 Release date: 13-Aug-14

Protein chain

P29320  (EPHA3_HUMAN) -  Ephrin type-A receptor 3 from Homo sapiens

Seq: 983 a.a.

Struc: 266 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = 25Q) matches with 40.54% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/jm5009242

J Med Chem 57:6834-6844 (2014)

PubMed id: 25076195

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

A.Unzue, J.Dong, K.Lafleur, H.Zhao, E.Frugier, A.Caflisch, C.Nevado.

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.