More significantly, loss of Plek2 reverted the widespread thrombosis, cytokine secretion syndrome, and lethality of JAK2 V617F knockin mice. We further revealed that Plek2 knockout mice did not exhibit significant hematologic or other abnormalities. The above studies indicate that treating MPNs with Plek2 inhibitors will be less likely to have severe side effects compared to those treated with JAK inhibitors. Given the significance, we carried out high-throughput screening and medicinal chemistry optimization to develop novel, potent small molecule Plek2 inhibitors. Our data show that the lead compound APX-052 directly binds to Plek2, blocks Akt phosphorylation, inhibits cell proliferation, and is effective in reducing myeloproliferation and thrombosis in JAK2 V617F knockin MPN mouse model in vivo.

Our findings have provided an unprecedented opportunity to get past a stumbling block that until now has stymied the MPN field. We are currently optimizing an entirely novel class of therapeutic agents that target the Plek2 signaling cascade for the treatment of MPNs and Plek2 overexpressing solid tumors.