文献类型：期刊文献

英文题名：Discovery of a Proteolysis-Targeting Chimera Degrader of JAK2 as a Potential Therapeutic Agent for JAK2-Mediated Myeloproliferative Neoplasms

作者：Wang, Caolin[1];Chen, Ziqi[1];Wang, Siyu[1];Wang, Jie[1];Yu, Panpan[1];Huang, Chulu[1];Wu, Yunpeng[1];Zhao, Zhenjiang[1];Mei, Wenyi[1,2];Li, Honglin[1,2,3];Zhu, Lili[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Lingang Lab, Shanghai 200031, Peoples R China;[3]East China Normal Univ, Innovat Ctr AI & Drug Discovery, Sch Pharm, Shanghai 200062, Peoples R China

年份：2025

卷号：68

期号：11

起止页码：12085

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001502884800001)】；

基金：This work was supported in part by the National Natural Science Foundation of China (82425104 to H.L.), the National Key R&D Program of China (2022YFC3400501, 2022YFC3400504).

语种：英文

摘要：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 mu M 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.