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马来酸氟罗替尼的临床前研究，一种新型的 JAK2/FLT3 抑制剂，用于治疗 JAK2 诱导的骨髓增生性肿瘤。

Preclinical studies of Flonoltinib Maleate, a novel JAK2/FLT3 inhibitor, in treatment of JAK2-induced myeloproliferative neoplasms.

机构信息

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.

Department of Hematology and Research Laboratory of Hematology, West China Hospital of Sichuan University, Chengdu, China.

出版信息

Blood Cancer J. 2022 Mar 7;12(3):37. doi: 10.1038/s41408-022-00628-2.

DOI:10.1038/s41408-022-00628-2
PMID:35256594
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8901636/
Abstract

Janus kinase 2 (JAK2) hyperactivation by JAK2 mutation leads to myeloproliferative neoplasms (MPNs) and targeting JAK2 could serve as a promising therapeutic strategy for MPNs. Here, we report that Flonoltinib Maleate (FM), a selective JAK2/FLT3 inhibitor, shows high selectivity for JAK2 over the JAK family. Surface plasmon resonance assays verified that FM had a stronger affinity for the pseudokinase domain JH2 than JH1 of JAK2 and had an inhibitory effect on JAK2 JH2V617F. The cocrystal structure confirmed that FM could stably bind to JAK2 JH2, and FM suppressed endogenous colony formation of primary erythroid progenitor cells from patients with MPNs. In several JAK2-induced MPN murine models, FM could dose-dependently reduce hepatosplenomegaly and prolong survival. Similar results were observed in JAK2 bone marrow transplantation mice. FM exhibited strong inhibitory effects on fibrosis of the spleen and bone marrow. Long-term FM treatment showed good pharmacokinetic/pharmacodynamic characteristics with high drug exposure in tumor-bearing tissues and low toxicity. Currently, FM has been approved by the National Medical Products Administration of China (CXHL2000628), and this study will guide clinical trials for patients with MPNs.

摘要

Janus 激酶 2（JAK2）的突变导致 JAK2 过度激活，进而引发骨髓增殖性肿瘤（MPN）。靶向 JAK2 可能成为 MPN 的一种有前途的治疗策略。在这里，我们报告 Flonoltinib 马来酸盐（FM），一种选择性 JAK2/FLT3 抑制剂，对 JAK2 具有比 JAK 家族更高的选择性。表面等离子体共振分析验证了 FM 与 JAK2 的假激酶结构域 JH2 具有更强的亲和力，并且对 JAK2 JH2V617F 具有抑制作用。共晶结构证实 FM 可以稳定地与 JAK2 JH2 结合，并且 FM 抑制了来自 MPN 患者的原发性红细胞祖细胞的内源性集落形成。在几种 JAK2 诱导的 MPN 小鼠模型中，FM 可以剂量依赖性地减少肝脾肿大并延长生存期。在 JAK2 骨髓移植小鼠中也观察到了类似的结果。FM 对脾和骨髓纤维化具有强烈的抑制作用。长期 FM 治疗显示出良好的药代动力学/药效学特征，在肿瘤组织中具有高药物暴露，毒性低。目前，FM 已获得中国国家药品监督管理局（CXHL2000628）的批准，本研究将为 MPN 患者的临床试验提供指导。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/3e5b73e1f5e1/41408_2022_628_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/d84057117aa8/41408_2022_628_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/db17600bca2c/41408_2022_628_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/d8524ef50b27/41408_2022_628_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/ff14b5bc3548/41408_2022_628_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/3f215fa36087/41408_2022_628_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/6517290061d0/41408_2022_628_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/3e5b73e1f5e1/41408_2022_628_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/d84057117aa8/41408_2022_628_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/db17600bca2c/41408_2022_628_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/d8524ef50b27/41408_2022_628_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/ff14b5bc3548/41408_2022_628_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/3f215fa36087/41408_2022_628_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/6517290061d0/41408_2022_628_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d591/8901636/3e5b73e1f5e1/41408_2022_628_Fig7_HTML.jpg

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1
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2
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J Med Chem. 2021 Feb 25;64(4):2228-2241. doi: 10.1021/acs.jmedchem.0c01952. Epub 2021 Feb 11.
3
Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function.
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Front Chem. 2025 Jan 21;12:1529211. doi: 10.3389/fchem.2024.1529211. eCollection 2024.
4
Mechanisms and therapeutic prospect of the JAK-STAT signaling pathway in liver cancer.JAK-STAT信号通路在肝癌中的作用机制及治疗前景
Mol Cell Biochem. 2025 Jan;480(1):1-17. doi: 10.1007/s11010-024-04983-5. Epub 2024 Mar 22.
5
The importance of protein domain mutations in cancer therapy.蛋白质结构域突变在癌症治疗中的重要性。
Heliyon. 2024 Mar 9;10(6):e27655. doi: 10.1016/j.heliyon.2024.e27655. eCollection 2024 Mar 30.
6
Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches.基于结构的药物发现方法探讨：治疗骨髓增殖性肿瘤的下一代 JAK2 抑制剂。
Blood Cancer Discov. 2023 Sep 1;4(5):352-364. doi: 10.1158/2643-3230.BCD-22-0189.
复杂性自身炎症综合征揭示 JAK1 激酶转录和生化功能的基本原理。
Immunity. 2020 Sep 15;53(3):672-684.e11. doi: 10.1016/j.immuni.2020.07.006. Epub 2020 Aug 3.
4
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5
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6
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7
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Lancet Haematol. 2020 Mar;7(3):e226-e237. doi: 10.1016/S2352-3026(19)30207-8. Epub 2020 Jan 23.
8
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J Med Chem. 2019 Nov 27;62(22):10305-10320. doi: 10.1021/acs.jmedchem.9b01348. Epub 2019 Nov 8.
9
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10
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