Thrombosis, often at unusual sites such as splanchnic vein and arteries, is common complication and one of the leading causes of mortality and morbidity in patients with chronic myeloproliferative neoplasms (MPNs). Developing effective therapies for thrombosis in MPNs is in its nascence. Current first-line therapy of chronicphase MPNs includes aspirin, hydroxyurea, interferon a, or anagrelide. However, these treatment approachesremain suboptimal with ongoing risks for thrombosis, hemorrhage, and impaired quality of life. Targeted molecular therapy at 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, especiallytargeting the downstream effectors of the JAK2 pathway that is commonly activated in these disorders. One ofthese effectors is Pleckstrin-2 (Plek2) that is a novel target of the JAK2-STAT5 pathway. Previous studies haveshown that loss of Plek2 ameliorated JAK2V617F mutant-induced myeloproliferative phenotypes, and revertedthrombosis and lethality of the JAK2V617F MPN mouse model. Importantly, Plek2 is overexpressed in the bonemarrow and peripheral blood mononuclear cells from JAK2V617F positive chronic MPN patients. Given thesignificance of Plek2 in thrombosis pathogenesis in MPNs, the Ji laboratory at Northwestern University hasidentified hit compounds of Plek2 small molecule inhibitors using in silico-based high-throughput screeningsand cell-based assays. Preliminary data show that the hit compounds significantly inhibit Plek2's functions onerythroblast proliferation and lamellipodia formation in vitro. The hit compounds also dramatically reducemyeloproliferation and thrombosis in vivo in MPN mouse models. Preliminary mechanistic studies reveal thatPlek2 functions as a scaffold protein to recruit PI3K effector proteins and enhances PI3K-Akt signaling. Plek2inhibitors bind to Plek2 and disrupt this recruitment, which blocks PI3K-Akt signaling and inhibits cellhyperproliferation. Together, these findings lead us to hypothesize that Plek2 inhibitors block cellhyperproliferation in vitro and in vivo and prevent thrombosis in MPNs. The goal of this Phase I SBIR project isto establish proof-of-principle evidence for the therapeutic effects of Plek2 inhibitors in thrombosis in MPNs. InAim 1, we propose to develop lead compounds with potent inhibitory effects of Plek2-induced cell proliferationin vitro using medicinal chemistry and cell-based assays. In Aim 2, we will examine the efficacy,pharmacokinetics, and toxicity of lead compounds in pre-clinical MPN mouse models with thrombosis. Aplexishas a strong support from Northwestern University's Innovation and New Ventures Office (INVO) on anexclusive license for the associated patent-pending intellectual property from this technology. The collaborationwith the Ji laboratory at Northwestern University will ensure the success of the proposed research, which willposition Aplexis to the next step in the production of clinical candidate of Plek2 inhibitors and pre-INDinvestigation in Phase II.
Public Health Relevance Statement: PROJECT NARRATIVE Thrombosis is a common complication and one of the leading causes of mortality and morbidity in patients with myeloproliferative disorders. Our proposed study focuses on the development of small molecule inhibitors of a novel drug target named Plek2 to treat thrombosis in these disorders, which will lay the foundation for future clinical trials of new therapeutic strategies.
Project Terms: <(IFN) α><(IFN)-α><(IFN)α><47KDa platelet protein> | | | | | | 