Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis.
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.
Center for Integrative Chemical Biology and Drug Discovery ‡Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy §Department of Pharmacology ∥Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Weihe
W
Zhang
Andrew L
AL
McIver
Michael A
MA
Stashko
Deborah
D
DeRyckere
Brian R
BR
Branchford
Debra
D
Hunter
Dmitri
D
Kireev
Michael J
MJ
Miley
Jacqueline
J
Norris-Drouin
Wendy M
WM
Stewart
Minjung
M
Lee
Susan
S
Sather
Yingqiu
Y
Zhou
Jorge A
JA
Di Paola
Mischa
M
Machius
William P
WP
Janzen
H Shelton
HS
Earp
Douglas K
DK
Graham
Stephen V
SV
Frye
Xiaodong
X
Wang
D003511:Cyclohexanols / Q000138:chemical synthesis* / Q000627:therapeutic use; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use*; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy* / Q000517:prevention & control*; D000076202:c-Mer Tyrosine Kinase
D003511:Cyclohexanols; D005343:Fibrinolytic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; C586742:UNC2881; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase