PDB 4M3Q deposited: 2013-08-06 modified: 2014-01-15
Title Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1917
Authors Cummings, C., Deryckere, D., Earp, H.S., Frye, S.V., Graham, D.K., Hunter, D., Janzen, W.P., Kireev, D., Kirkpatrick, G., Lee, M., Machius, M., Miley, M.J., Norris-Drouin, J., Sather, S., Stashko, M.A., Stewart, W.M., Wang, X., Zhang, D., Zhang, W., Zhou, Y.
Structure factors resolution 2.718 rfactor 0.243 rfree 0.2958
DPI 0.97 theoretical min: 0.51

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.

J.Med.Chem. 2013 Dec; 56(23):9683-9692 doi:10.1021/jm401387j

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL3091310
PubMed 24195762 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4M3Q/1 4M3Q 1 monomer 0 1 6 1667
4M3Q/2 4M3Q 2 monomer 0 1 4 1615