Targeting Plek2 for the treatment of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are a group of bone marrow diseases with excessive production of blood cells and increased risk of evolving to acute leukemia. Patients with MPNs also show significantly increased risk of developing blood clotting that often leads to morbidity and mortality. Current therapies on MPNs are not curative. In addition, patients often encounter drug resistance and significant side effects. Therefore, new therapeutic strategies are urgently needed. Our proposed study focuses on a novel target that plays an important role in the disease development of MPNs and their associated blood clotting. We have identified hit compounds of small molecule inhibitors of this novel target using high-throughput screenings. These compounds showed effective inhibitory functions in cell based assays and animal experiments modeling MPNs. We propose to further optimize and validate the compounds in cell based assays. We will also test the optimized compounds in pre-clinical MPN mouse models. Successful completion of this project will lay the foundation for clinical trials of these novel inhibitors as single agents or in combination with other compounds to treat patients with MPNs and their associated blood clotting.