PAR1 inhibitor

PAR1 inhibitors are a class of therapeutic agents that target Protease-Activated Receptor 1 (PAR1), a G-protein-coupled receptor (GPCR) activated by thrombin. While traditionally developed and approved for cardiovascular indications to prevent thrombotic events (e.g., vorapaxar), recent research has highlighted PAR1 as a significant therapeutic target in oncology, particularly in Acute Myeloid Leukemia (AML). In AML, PAR1 is selectively expressed on leukemic stem cells (LSCs) and acts as a critical regulator of their self-renewal and survival. Inhibition of PAR1 disrupts downstream signaling pathways, including the ß-catenin and Tcf7L2 transcriptional axes, leading to increased apoptosis, induction of cell differentiation, and a reduction in the self-renewal capacity of therapy-resistant LSCs. This mechanism suggests that PAR1 inhibitors could be utilized as a next-generation treatment to eradicate LSCs and mitigate relapse in aggressive blood cancers.