Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasms
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 a...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222012732 |
| _version_ | 1811308619862376448 |
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| author | Huan Ge Caolin Wang Chaoquan Tian Yanyan Diao Wanqi Wang Xiangyu Ma Jian Zhang Honglin Li Zhenjiang Zhao Lili Zhu |
| author_facet | Huan Ge Caolin Wang Chaoquan Tian Yanyan Diao Wanqi Wang Xiangyu Ma Jian Zhang Honglin Li Zhenjiang Zhao Lili Zhu |
| author_sort | Huan Ge |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T09:26:29Z |
| format | Article |
| id | doaj.art-3c9d99bd657d4d52ac2e3877069c4cab |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-13T09:26:29Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-3c9d99bd657d4d52ac2e3877069c4cab2022-12-22T02:52:25ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-12-01156113884Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasmsHuan Ge0Caolin Wang1Chaoquan Tian2Yanyan Diao3Wanqi Wang4Xiangyu Ma5Jian Zhang6Honglin Li7Zhenjiang Zhao8Lili Zhu9Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China; Innovation Center for AI and Drug Discovery, East China Normal University, Shanghai 200062, ChinaShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, ChinaShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S0753332222012732Selective JAK2 inhibitorJAK2V617FJAK2 signaling pathwayMyeloproliferative neoplasmsWWQ-131 |
| spellingShingle | Huan Ge Caolin Wang Chaoquan Tian Yanyan Diao Wanqi Wang Xiangyu Ma Jian Zhang Honglin Li Zhenjiang Zhao Lili Zhu Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasms Biomedicine & Pharmacotherapy Selective JAK2 inhibitor JAK2V617F JAK2 signaling pathway Myeloproliferative neoplasms WWQ-131 |
| title | Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasms |
| title_full | Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasms |
| title_fullStr | Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasms |
| title_full_unstemmed | Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasms |
| title_short | Efficacy of WWQ-131, a highly selective JAK2 inhibitor, in mouse models of myeloproliferative neoplasms |
| title_sort | efficacy of wwq 131 a highly selective jak2 inhibitor in mouse models of myeloproliferative neoplasms |
| topic | Selective JAK2 inhibitor JAK2V617F JAK2 signaling pathway Myeloproliferative neoplasms WWQ-131 |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222012732 |
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