文献类型：期刊文献

英文题名：Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasms

作者：Ge, Huan[1];Wang, Caolin[1];Tian, Chaoquan[1];Diao, Yanyan[1];Wang, Wanqi[1];Ma, Xiangyu[1];Zhang, Jian[1];Li, Honglin[1,2];Zhao, Zhenjiang[1];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]East China Normal Univ, Innovat Ctr AI & Drug Discovery, Shanghai 200062, Peoples R China

年份：2022

卷号：156

外文期刊名：BIOMEDICINE & PHARMACOTHERAPY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000883021100003)】；

基金：This research is supported in part by the National Natural Science Foundation of China (Grants 81825020 and 82150208); the Shanghai Science and Technology Commission Biomedical Science and Technology Support Special Project (Grants 21S11907900 and 20S11901000), the Fundamental Research Funds for the Central Universities. Honglin Li is also sponsored by National Program for Special Supports of Eminent Professionals and National Program for Support of Top-notch Young Professionals.

语种：英文

外文关键词：Selective JAK2 inhibitor; JAK2 signaling pathway; Myeloproliferative neoplasms; WWQ-131

摘要：Hyperactivation of the Janus kinase 2 (JAK2) signaling pathway leads to myeloproliferative neoplasms (MPNs) and targeting JAK2 can be used as an effective strategy for the treatment of MPNs. Here, our study indicated that WWQ-131 was a highly selective JAK2 inhibitor (IC50 =2.36 nM), with 182-fold and 171-fold more selective to JAK1 and JAK3, respectively. In JAK2V617F-dependent cell lines, WWQ-131 efficaciously inhibited cell pro-liferation, induced cell cycle arrest at the G2/M phase and apoptosis, and blocked the aberrant activation of JAK2 signaling pathway. In a mouse Ba/F3_JAK2V617F driven disease model, WWQ-131 effectively suppressed STAT5 phosphorylation in spleen and liver, and inhibited Ba/F3_JAK2V617F cells spreading and proliferation in vivo. In addition, WWQ-131 suppressed rhEPO-induced extramedullary erythropoiesis and polycythemia in mice, as well as hematocrits and spleen sizes, especially had no effect on white blood cell count. Furthermore, WWQ-131 (75 mg/kg) exhibited stronger therapeutic effects than fedratinib (120 mg/kg) in these two MPN models. Taken together, this study suggests that WWQ-131 will be a promising candidate for the treatment of MPNs.