4MH7: Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1896

Citation:
Abstract
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.
PDB ID: 4MH7Download
MMDB ID: 120092
PDB Deposition Date: 2013/8/29
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.51  Å
Source Organism:
Similar Structures:
Biological Unit for 4MH7: monomeric; determined by author and by software (PISA)
Molecular Components in 4MH7
Label Count Molecule
Protein (1 molecule)
1
Tyrosine-protein Kinase MER(Gene symbol: MERTK)
Molecule annotation
Chemicals (8 molecules)
1
5
2
2
3
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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