Faculty Collaboration Database

The small-molecule MERTK inhibitor UNC2025 decreases platelet activation and prevents thrombosis. J Thromb Haemost 2018 Feb;16(2):352-363

Date

10/19/2017

Pubmed ID

29045015

Pubmed Central ID

PMC5858881

DOI

10.1111/jth.13875

Scopus ID

2-s2.0-85040644454 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

UNLABELLED: 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 α_IIb 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-P2Y_1&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-P2Y_1&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.

Author List

Branchford BR, Stalker TJ, Law L, Acevedo G, Sather S, Brzezinski C, Wilson KM, Minson K, Lee-Sherick AB, Davizon-Castillo P, Ng C, Zhang W, Neeves KB, Lentz SR, Wang X, Frye SV, Shelton Earp H 3rd, DeRyckere D, Brass LF, Graham DK, Di Paola JA

Author

Brian Branchford MD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenine
Animals
Blood Platelets
Disease Models, Animal
Drug Synergism
Drug Therapy, Combination
Female
Humans
Intercellular Signaling Peptides and Proteins
Male
Mice, Inbred C57BL
Phosphorylation
Piperazines
Platelet Activation
Platelet Aggregation
Platelet Aggregation Inhibitors
Platelet Glycoprotein GPIIb-IIIa Complex
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pulmonary Embolism
Purinergic P2Y Receptor Antagonists
Receptor Protein-Tyrosine Kinases
Signal Transduction
Thrombosis
c-Mer Tyrosine Kinase