Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis

Weihe Zhang, Andrew L. McIver, Michael A. Stashko, Deborah Deryckere, Brian R. Branchford, Debra Hunter, Dmitri Kireev, Michael J. Miley, Jacqueline Norris-Drouin, Wendy M. Stewart, Minjung Lee, Susan Sather, Yingqiu Zhou, Jorge A. Di Paola, Mischa Machius, William P. Janzen, H. Shelton Earp, Douglas K. Graham, Stephen V. Frye, Xiaodong Wang

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 IC 50 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.

Original languageEnglish
Pages (from-to)9693-9700
Number of pages8
JournalJournal of Medicinal Chemistry
Volume56
Issue number23
DOIs
StatePublished - Dec 12 2013

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