OC 61.3 - CS585 is a novel and highly selective IP receptor agonist for prevention of thrombosis

Tuesday, June 27, 2023

15:15 – 15:30 ET

Room: 710A

Session Available As: On-Demand

Co-Author(s)

SL

Sylviane Lambert

Research Specialist
University of Michigan
Ann Arbor, Michigan, United States
LS

Livia Stanger

Graduate Student
University of Michigan
Ann Arbor, Michigan, United States
AY

Adriana Yamaguchi

Postdoctoral Fellow
University of Michigan
Ann Arbor, Michigan, United States
PY

Pooja Yalavarthi

Undergraduate Student
University of Michigan
Ann Arbor, Michigan, United States
AR

Andrew Rickenberg

Undergraduate Student
University of Michigan
Ann Arbor, Michigan, United States
NB

Niklas Bergh

Professor
Institute of Medicine, University of Gothenburg
Gothenburg, Gavleborgs Lan, Sweden
BD

Bjorn Dahlof

Professor
Institute of Medicine, University of Gothenburg
Gothenburg, Gavleborgs Lan, Sweden

Presenting Author(s)

Michael Holinstat, PhD

Associate Professor of Pharmacology
University of Michigan
Ann Arbor, Michigan, United States

Background: Cardiovascular disease remains the primary cause of morbidity and mortality today and impinges on a number of organ systems including the vessels, heart, lungs, and brain with thrombotic complications. While platelet activation is critical for maintaining hemostasis and preventing leakage of blood cells from the vessel to extravascular compartments, the platelet clotting system is highly regulated to prevent an occlusive thrombus that deprives key organ systems of oxygen. Recently, we developed an analogue named CS585 for an oxidized lipid produced in the blood that limits platelet activation through activation of the prostacyclin receptor.

Aims: To determine if CS585 has the potential to be utilized as a novel antiplatelet therapeutic for prevention of thrombosis.

Methods: Human blood and isolated platelets were assessed for the ability of CS585 to inhibit integrin IIb3 activation and granule secretion (flow cytometry), aggregation, and whole blood adhesion by flow chamber and T-TAS 01 assessment. Mouse models of thrombosis and bleeding were used to assess CS585 effects of hemostasis. Selectivity to IP receptor was assessed by IP-/- mice and human blood treated with IP receptor inhibitors.

Results: CS585 potently and selectively targeted the prostacyclin receptor on the human platelet resulting in a highly selective prevention of thrombosis. CS585 also functioned in human whole blood ex vivo and in prevention of both small and large vessel thrombosis in mouse models. Finally, we demonstrate that CS585 does not perturb coagulation or increase the risk for bleeding

Conclusion(s): We have developed a novel small molecule agonist that is selective for the prostacyclin receptor, stable in human and mouse blood, is effective in prevention of unwanted platelet-mediated thrombosis and doesn’t alter hemostasis. This discovery represents a new validated target in the treatment of thrombotic diseases in the blood and vessel without the observed risks of bleeding and off-target activation of other prostaglandin receptors.

Learning Objectives:

Decribe how CS585 inhibits platelet activity through activation of the IP receptor
Evaluate selectivity of CS585 for activation of the IP receptor
Compare CS585 selectivity and regulation of platelets to other IP receptor agonists