JAK2 is a promising target for treating myeloproliferative neoplasms (MPNs). However, existing JAK2 inhibitors cannot fully cure these diseases and may induce resistance with prolonged use. Here, we report the design, synthesis, and biological evaluation of a series of highly potent JAK2 degraders based on our previously developed inhibitor WWQ-131. The optimal compound 10i demonstrates a high degradation rate (DR) against JAK2 in SET-2 cells carrying the JAK2 V617F mutation, achieving a DR of 91.32% at 5 μM and a DC50 of 27.35 ± 5.36 nM. Moreover, 10i exhibits more potent antiproliferative activity against SET-2 cells than fedratinib and its parent inhibitor WWQ-131. Mechanistic studies reveal that 10i degrades JAK2 through the ubiquitin-protease pathway. Importantly, 10i suppresses rhEPO-mediated polycythemia and splenomegaly in mice by degrading JAK2 and interfering with the JAK2-STAT signaling pathway. Taken together, the results of this study reveal a promising JAK2 PROTAC degrader for the treatment of MPNs.
