Novel histone deacetylase inhibitor, CS014, attenuates in vivo thrombosis while maintaining hemostasis

BACKGROUND: Epigenetic regulation with histone deacetylase (HDAC) inhibition by valproic acid (VPA) has been used to regulate a number of pathological conditions to date. Recently, VPA was shown to alter production and local release of tissue plasminogen activator and plasminogen activator inhibitor-1 in the blood and to have utility in the regulation of clot formation, resolution, and stability. However, VPA is known to be associated with a rare risk of hepatotoxicity. OBJECTIVE: To improve upon VPA, a novel HDAC inhibitor, CS014, was developed with preserved HDAC inhibition and reduced hepatotoxic potential. In this study, we sought to assess the potential of CS014 to function as an antithrombotic drug with a safer profile than VPA. METHODS: CS014 and VPA were assessed for HDAC inhibitory properties as well as 4-ene metabolite production in both in vivo and in vitro settings. In vivo clot formation and bleeding were measured in mice dosed with CS014 or VPA. The direct effects of CS014 and VPA on platelet activity were evaluated ex vivo. RESULTS: CS014 maintained equivalent inhibition of HDAC compared with VPA, without the formation of a key hepatotoxic metabolite, in addition to maintaining the ability to prevent thrombus formation after a vascular injury. Although significant attenuation of platelet accumulation and fibrin formation was observed at the site of injury, CS014 was not observed to alter coagulation or increase bleeding time. CONCLUSIONS: CS014 represents a novel HDAC inhibitor with the potential for reducing hepatotoxicity while maintaining the benefit of preventing injury-induced clotting without increased bleeding diathesis.