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J Thromb Haemost. 2018 Feb;16(2):352-363. doi: 10.1111/jth.13875. Epub 2018 Jan 12.

The small-molecule MERTK inhibitor UNC2025 decreases platelet activation and prevents thrombosis.

Author information

1
Department of Pediatrics, Section of Hematology/Oncology, University of Colorado School of Medicine, Aurora, CO, USA.
2
University of Colorado Hemophilia and Thrombosis Center, Aurora, CO, USA.
3
Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4
Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
5
Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Atlanta, GA, USA.
6
Department of Pediatrics, Section of Hematology/Oncology, Emory University School of Medicine, Atlanta, GA, USA.
7
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
8
Department of Chemical & Biological Engineering, Colorado School of Mines, Golden, CO, USA.
9
Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
10
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
11
Graduate Program - Human Medical Genetics, University of Colorado School of Medicine, Aurora, CO, USA.

Abstract

Essentials Signaling by Gas6 through Tyro3/Axl/Mer receptors is essential for stable platelet aggregation. UNC2025 is a small molecule inhibitor of the Mer tyrosine kinase. UNC2025 decreases platelet activation in vitro and thrombus formation in vivo. UNC2025's anti-platelet effect is synergistic with inhibition of the ADP receptor, P2Y12 .

SUMMARY:

Background Growth arrest-specific protein 6 signals through the TAM (TYRO-3-AXL-MERTK) receptor family, mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing αIIb β3 integrin. Objective To describe the antithrombotic effects mediated by UNC2025, a small-molecule MERTK tyrosine kinase inhibitor. Methods MERTK phosphorylation and downstream signaling were assessed by immunoblotting. Light transmission aggregometry, flow cytometry and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregates in vitro. The effects of MERTK inhibition on arterial and venous thrombosis, platelet accumulation at microvascular injury sites and tail bleeding times were determined with murine models. The effects of combined treatment with ADP-P2Y1&12 pathway antagonists and UNC2025 were also evaluated. Results and Conclusions Treatment with UNC2025 inhibited MERTK phosphorylation and downstream activation of AKT and SRC, decreased platelet activation, and protected animals from pulmonary embolism and arterial thrombosis without increasing bleeding times. The antiplatelet effect of UNC2025 was enhanced in combination with ADP-P2Y1&12 pathway antagonists, and a greater than additive effect was observed when these two agents with different mechanisms of inhibition were coadministered. TAM kinase signaling represents a potential therapeutic target, as inhibition of this axis, especially in combination with ADP-P2Y pathway antagonism, mediates decreased platelet activation, aggregate stability, and thrombus formation, with less hemorrhagic potential than current treatment strategies. The data presented here also demonstrate antithrombotic activity mediated by UNC2025, a novel translational agent, and support the development of TAM kinase inhibitors for clinical applications.

KEYWORDS:

MERTK ; growth arrest-specific protein 6; integrin αIIbβ3; platelet activation; thrombosis

Comment in

PMID:
29045015
PMCID:
PMC5858881
DOI:
10.1111/jth.13875
[Indexed for MEDLINE]
Free PMC Article

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