CS585 Demonstrates Favorable Selectivity and Sustained In Vivo Action in Preventing Platelet Activation and Thrombosis Compared to Existing IP Receptor Agonists

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.1188-1188
• Main Authors: Stanger, Livia, Yalavarthi, Pooja, Lambert, Sylviane, Rickenberg, Andrew, Goerger, Krista, Gilmore, Devin, Dahlof, Bjorn, Bergh, Niklas, Holinstat, Michael
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-186300

Anti-platelet therapeutics are common tools in the treatment of thrombotic diseases, decreasing morbidity and mortality resulting from cardiovascular complications. However, many patients remain at risk for a cardiovascular event while others experience bleeding due to hemostatic dysregulation. The need for target specificity and lasting stability presents a major challenge in the development of novel antithrombotic therapeutics. While increasing platelet cAMP levels through activation of the prostacyclin (IP) receptor is a viable therapeutic approach, the IP receptor is currently considered a challenging target due to the non-selectivity and instability of existing IP agonists. Our lab has developed a novel IV and orally available IP receptor agonist, CS585, with selectivity towards the IP receptor and sustained in vivo protection from injury-induced thrombosis without observed bleeding. CS585 demonstrates IP receptor-dependent activity, leading to activation of protein kinase A (PKA), a key player in inhibitory signaling. While indications of current IP receptor agonists are limited to pulmonary arterial hypertension and temporary relief of peripheral artery disease, CS585 presents a new approach to selectively regulate platelet activation and thrombosis. CS585 and other IP receptor agonists, iloprost and selexipag, were assessed by direct comparison to elucidate potential differences in selectivity and sustained action. Selectivity was determined using aggregation and VASP phosphorylation. The effects of CS585 are inhibited by pharmacological inhibition of the IP receptor, but not by inhibition of the DP1, EP2, or EP4 prostaglandin receptors. Meanwhile, the activities of iloprost and selexipag were affected by other prostaglandin inhibitors, supporting the improved selectivity toward activation of the IP receptor with CS585. Arterial thrombosis was measured and quantified in a laser-induced cremaster thrombosis assay in IP agonist-treated WT mice to assess platelet activation and thrombus formation in vivo in mouse models of thrombosis. In WT mice treated with CS585, we observed sustained effects of CS585 following both IV and oral administration. Platelets and fibrin were labeled and accumulation at the site of injury was measured using intravital microscopy. In contrast to the FDA-approved IP receptor agonists (iloprost and selexipag) which showed short-term protection from thrombosis, treatment with CS585 resulted in sustained inhibition of clot and