Identification of small molecule inhibitors of Plek2 for the treatment of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are a group of bone marrow diseases with excessive myeloid cell production and increased risk of evolving to acute myeloid leukemia. V617F driver mutation of JAK2 is one of the leading causes of MPNs. The discovery of this mutation led to the development of JAK2 inhibitors for the treatment of MPNs. However, JAK2 inhibitors are not curative. In addition, MPN patients treated with JAK2 inhibitor often develop drug resistance and severe side effects due to the indispensable roles of JAK2 in normal hematopoiesis. New approaches to treating MPNs, especially drugs targeting the downstream effectors of the JAK2 pathway, are of paramount significance to develop. Our recent findings revealed that loss of Plek2, a novel downstream target of the JAK2 pathway, ameliorated JAK2V617F-induced myeloproliferative phenotypes, and more significantly reverted the widespread vascular occlusions and lethality of JAK2V617F MPN mouse model. Based on these novel discoveries, we hypothesize that inhibition of Plek2 function through small molecule inhibitors will be an important approach to treat MPNs. We have built a multi-template based homology model and screened a diverse set of 100,000 drug-like compounds and identified 40 hits. One of the compound showed potent Plek2 inhibitory effect in several in vitro functional assays. In this proposal, we propose to perform biophysical assays, counter-screening, optimization the lead compound, and in vivo animal experiments. Successful completion of this project will lay the foundation for clinical trials of using Plek2 inhibitors as single agents or in combination with other compounds to treat MPNs.