PDBsum entry 4m3q

Transferase/transferase inhibitor

PDB id: 4m3q

Contents

Protein chains

243 a.a.

236 a.a.

Ligands

24K ×2

Metals

_CL ×7

_MG

Waters ×6

PDB id:

4m3q

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase mer in complex with inhibitor unc1917

Structure:

Tyrosine-protein kinase mer. Chain: a, b. Fragment: catalytic domain, unp residues 570-864. Synonym: proto-oncogenE C-mer, receptor tyrosine kinase mertk. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mer, mertk. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.72Å R-factor: 0.248 R-free: 0.296

Authors:

W.Zhang,D.Zhang,M.A.Stashko,D.Deryckere,D.Hunter,D.B.Kireev,M.Miley, C.Cummings,M.Lee,J.Norris-Drouin,W.M.Stewart,S.Sather,Y.Zhou, G.Kirkpatrick,M.Machius,W.P.Janzen,H.S.Earp,D.K.Graham,S.Frye,X.Wang

Key ref:

W.Zhang et al. (2013). Pseudo-cyclization through intramolecular hydrogen bond enables discovery of pyridine substituted pyrimidines as new Mer kinase inhibitors. J Med Chem, 56, 9683-9692. PubMed id: 24195762 DOI: 10.1021/jm401387j

Date:

06-Aug-13 Release date: 27-Nov-13

Protein chain

Q12866  (MERTK_HUMAN) -  Tyrosine-protein kinase Mer from Homo sapiens

Seq: 999 a.a.

Struc: 243 a.a.

Protein chain

Q12866  (MERTK_HUMAN) -  Tyrosine-protein kinase Mer from Homo sapiens

Seq: 999 a.a.

Struc: 236 a.a.

Enzyme reactions

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

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

Added reference

DOI no: 10.1021/jm401387j

J Med Chem 56:9683-9692 (2013)

PubMed id: 24195762

Pseudo-cyclization through intramolecular hydrogen bond enables discovery of pyridine substituted pyrimidines as new Mer kinase inhibitors.

W.Zhang, D.Zhang, M.A.Stashko, D.DeRyckere, D.Hunter, D.Kireev, M.J.Miley, C.Cummings, M.Lee, J.Norris-Drouin, W.M.Stewart, S.Sather, Y.Zhou, G.Kirkpatrick, M.Machius, W.P.Janzen, H.S.Earp, D.K.Graham, S.V.Frye, X.Wang.

ABSTRACT

Abnormal activation or overexpression of Mer receptor tyrosine kinase has been implicated in survival signaling and chemoresistance in many human cancers. Consequently, Mer is a promising novel cancer therapeutic target. A structure-based drug design approach using a pseudo-ring replacement strategy was developed and validated to discover a new family of pyridinepyrimidine analogues as potent Mer inhibitors. Through SAR studies, 10 (UNC2250) was identified as the lead compound for further investigation based on high selectivity against other kinases and good pharmacokinetic properties. When applied to live cells, 10 inhibited steady-state phosphorylation of endogenous Mer with an IC50 of 9.8 nM and blocked ligand-stimulated activation of a chimeric EGFR-Mer protein. Treatment with 10 also resulted in decreased colony-forming potential in rhabdoid and NSCLC tumor cells, thereby demonstrating functional antitumor activity. The results provide a rationale for further investigation of this compound for therapeutic application in patients with cancer.