Developing small molecule inhibitors of Pleckstrin-2 to treat thrombosis

PROJECT SUMMARY Thrombosis, often at unusual sites such as splanchnic vein and arteries, is a common complication and one of the leading causes of mortality and morbidity in patients with myeloproliferative neoplasms (MPNs). Developing effective therapies for thrombosis in MPNs is in its infancy. Current first-line therapy of chronic phase MPNs includes aspirin, hydroxyurea, interferon a, or anagrelide. However, these treatment approaches remain suboptimal with ongoing risks for thrombosis, hemorrhage, and impaired quality of life. Targeted molecular therapy in this stage of MPNs for thrombosis is also lacking. Aplexis, Inc is a startup company focusing on the development of new approaches to treat thrombosis in the chronic phase of MPNs, especially targeting the downstream effectors of the JAK2 pathway that is commonly activated in these disorders. One of these effectors is Pleckstrin-2 (Plek2) that is a novel target of the JAK2-STAT5 pathway. Previous studies have shown that loss of Plek2 ameliorated JAK2V617F mutant-induced myeloproliferative phenotypes, and reverted thrombosis and lethality of the JAK2V617F MPN mouse model. Importantly, Plek2 is overexpressed in the bone marrow and peripheral blood mononuclear cells from JAK2V617F positive chronic MPN patients. Given the significance of Plek2 in thrombosis pathogenesis in MPNs, Aplexis has been collaborating with Ji laboratory at Northwestern University and has identified hit compounds of Plek2 small molecule inhibitors using in silico- based high-throughput screening and cell-based assays. With the support of the Phase I SBIR grant, Aplexis achieved another milestone by developing a lead compound APX-052 with potent efficacies and safety profiles. Mechanistic studies further revealed that APX-052 binds to Plek2 and disrupts Plek2-Akt interaction, which reduces Akt activation and inhibits cell proliferation. The goal of this Phase II SBIR project is to determine the toxicity and pharmacokinetics of APX-052 and test it in various in vivo MPN models. We will also initiate IND-enabling studies and conduct a pre-IND briefing with FDA. Aplexis has a strong support from Northwestern University’s Innovation and New Ventures Office (INVO) on an exclusive license for the associated patent-pending intellectual property from this technology. The collaboration with the Ji laboratory at Northwestern University will ensure the success of the proposed research, which will position Aplexis to the next step in the production of clinical candidate of Plek2 inhibitors.