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

• Published in: Biomedicine & pharmacotherapy Vol. 156; p. 113884
• Main Authors: Ge, Huan, Wang, Caolin, Tian, Chaoquan, Diao, Yanyan, Wang, Wanqi, Ma, Xiangyu, Zhang, Jian, Li, Honglin, Zhao, Zhenjiang, Zhu, Lili
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 01.12.2022; Elsevier
• Subjects: JAK2 signaling pathway; JAK2V617F; Myeloproliferative neoplasms; Selective JAK2 inhibitor; WWQ-131; Selective JAK2 inhibitor; JAK2 signaling pathway; JAK2V617F; WWQ-131; Myeloproliferative neoplasms
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.113884

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 proliferation, 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. [Display omitted] •WWQ-131 was identified as a potent and highly selective inhibitor of JAK2.•WWQ-131 blocked the aberrant activation of JAK2-mediated signaling pathway.•WWQ-131 suppressed tumor cells proliferation in a Ba/F3_JAK2V617F xenograft model.•WWQ-131 suppressed rhEPO-induced polycythemia in mice.