Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis. J Med Chem 2013 Dec 12;56(23):9693-700
Date
11/14/2013Pubmed ID
24219778Pubmed Central ID
PMC3962266DOI
10.1021/jm4013888Scopus ID
2-s2.0-84890459446 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
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.
Author List
Zhang W, McIver AL, Stashko MA, DeRyckere D, Branchford BR, Hunter D, Kireev D, Miley MJ, Norris-Drouin J, Stewart WM, Lee M, Sather S, Zhou Y, Di Paola JA, Machius M, Janzen WP, Earp HS, Graham DK, Frye SV, Wang XAuthor
Brian Branchford MD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
CyclohexanolsDrug Design
Fibrinolytic Agents
Humans
Models, Molecular
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidines
Receptor Protein-Tyrosine Kinases
Structure-Activity Relationship
Thrombosis
c-Mer Tyrosine Kinase
