Summary
PDB 4MHA deposited: 2013-08-29 modified: 2014-05-21
Title Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1817
Authors Branchford, B.R., DeRyckere, D., Di Paola, J.A., Earp, H.S., Frye, S.V., Graham, D.K., Hunter, D., Janzen, W.P., Kireev, D., Lee, M., Machius, M., McIver, A.L., Miley, M.J., Norris-Drouin, J., Sather, S., Stashko, M.A., Stewart, W.M., Wang, X., Zhang, W., Zhou, Y.
Method X-RAY DIFFRACTION
Structure factors resolution 2.59 rfactor 0.2412 rfree 0.2939
DPI 0.86 theoretical min: 0.45
Related PDB Entries 4MH7
Citations

The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo ring replacement strategy. The cocrystal structure of Mer with two compounds (7 and 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.

J.Med.Chem. 2013 Dec; 56(23):9693-9700 doi:10.1021/jm4013888

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL3091375
PubMed 24219778 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4MHA/1 4MHA 1 monomer 0 1 4 1852
4MHA/2 4MHA 2 monomer 0 1 5 1782