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

Brian R. Branchford; Timothy J. Stalker; Luke Law; Gilbert Acevedo; Susan Sather; Christine Brzezinski; Katina M. Wilson; Katherine Minson; Alisa B. Lee-Sherick; Pavel Davizon-Castillo; Christopher Ng; Weihe Zhang; Keith B. Neeves; Steven R. Lentz; Xiaodong Wang; Stephen V. Frye; H. Shelton Earp; Deborah DeRyckere; Lawrence F. Brass; Douglas K. Graham; Jorge A. Di Paola

doi:10.1111/jth.13875

Back

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

Journal article

Open access

Peer reviewed

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

Brian R. Branchford, Timothy J. Stalker, Luke Law, Gilbert Acevedo, Susan Sather, Christine Brzezinski, Katina M. Wilson, Katherine Minson, Alisa B. Lee-Sherick, Pavel Davizon-Castillo, …

Journal of thrombosis and haemostasis, Vol.16(2), pp.352-363

01/12/2018

DOI: 10.1111/jth.13875

PMCID: PMC5858881

PMID: 29045015

Files and links (1)

url

https://doi.org/10.1111/jth.13875View

Published (Version of record) Open Access

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 αIIbβ3 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.

Thrombosis

Growth Arrest Specific Protein 6

Integrin Alpha-iib Beta-3

MERTK

Platelet Activation

Details

Title: Subtitle: The small molecule MERTK inhibitor UNC2025 decreases platelet activation and prevents thrombosis
Creators: Brian R. Branchford - University of Colorado Denver
Timothy J. Stalker - University of Pennsylvania
Luke Law - University of Colorado Denver
Gilbert Acevedo - University of Colorado Denver
Susan Sather - University of Colorado Denver
Christine Brzezinski - University of Colorado Denver
Katina M. Wilson - Roy J. and Lucille A. Carver College of Medicine
Katherine Minson - Emory University
Alisa B. Lee-Sherick - University of Colorado Denver
Pavel Davizon-Castillo - University of Colorado Denver
Christopher Ng - University of Colorado Denver
Weihe Zhang - University of North Carolina at Chapel Hill
Keith B. Neeves - Colorado School of Mines
Steven R. Lentz - University of Iowa
Xiaodong Wang - University of North Carolina at Chapel Hill
Stephen V. Frye - University of North Carolina at Chapel Hill
H. Shelton Earp - University of North Carolina at Chapel Hill
Deborah DeRyckere - Emory University
Lawrence F. Brass - University of Pennsylvania
Douglas K. Graham - Emory University
Jorge A. Di Paola - University of Colorado Denver
Resource Type: Journal article
Publication Details: Journal of thrombosis and haemostasis, Vol.16(2), pp.352-363
DOI: 10.1111/jth.13875
PMID: 29045015
PMCID: PMC5858881
NLM abbreviation: J Thromb Haemost
ISSN: 1538-7933
eISSN: 1538-7836
Grant note: DOI: 10.13039/100000019, name: National Hemophilia Foundation; DOI: 10.13039/100001422, name: American Society of Hematology; DOI: 10.13039/100008322, name: CSL Behring; DOI: 10.13039/100000002, name: National Institutes of Health, award: K12HD068372-03, R01 HL084086, HHSN261200800001E; name: Child Health Research Career Development grant; DOI: 10.13039/100005881, name: Hemostasis and Thrombosis Research Society; DOI: 10.13039/100007343, name: Shire, award: 5H30MC00008-20-00 HRSA/MCHB; name: Postle Chair; name: University Cancer Research Fund; name: Federal Funds; DOI: 10.13039/100000054, name: National Cancer Institute
Language: English
Date published: 01/12/2018
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984360152002771

Metrics

16 Record Views

26 Times Cited - Web of Science