Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors.
Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors.
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共价 FGFR 抑制剂吡唑并[3,4-d]哒嗪酮衍生物的设计、合成和生物学评价
DOI：
10.1016/j.apsb.2020.09.002
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Wu X;Dai M;Cui R;Wang Y;Li C;Peng X;Zhao J;Wang B;Dai Y;Feng D;Yang T;Jiang H;Geng M;Ai J;Zheng M;Liu H
成纤维细胞生长因子受体（FGFR）已成为抗癌治疗的有前途的目标。本研究合成了66个吡唑并[3，4-d]哒嗪酮类化合物，并对其生物活性进行了评价。使用激酶抑制、细胞增殖和全血稳定性测定来评价它们对FGFR的活性，使我们能够探索结构-活性关系，从而了解调节共价抑制剂的选择性和反应性的结构要求。其中，通过免疫印迹分析，化合物10 h表现出针对FGFR的有效酶活性，并显著抑制与FGFR失调相关的各种癌细胞的增殖，并抑制癌细胞中的FGFR信号传导途径。此外，在FGFR 1扩增的NCI-H1581异种移植物模型中，10 h显示出高度有效的抗肿瘤功效（TGI = 91.6%，剂量为50 mg/kg）。合成了一系列吡唑并[3，4-d]哒嗪酮衍生物。进行了激酶抑制、细胞增殖和全血稳定性试验，使我们能够探索结构-活性关系，并了解调节共价抑制剂选择性和反应性的结构要求。化合物IOh在NCI-H1581异种移植模型中显示出高度有效的抗肿瘤功效。
Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure−activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors’ selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model. A series of pyrazolo[3,4-d]pyridazinone derivatives were synthesized. Kinase inhibition, cell proliferation, and whole blood stability assays were performed, allowing us to explore structure−activity relationship and to gain understanding of the structural requirements to modulate covalent inhibitors’ selectivity and reactivity. Compound 10h displayed highly potent antitumor efficacy in the NCI-H1581 xenograft model.
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DOI：
10.2217/fon.14.51
发表时间：
2014-05
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Davids MS;Brown JR
通讯作者：
Brown JR
影响因子：
7.3
作者：
Finlay, M. Raymond V.;Anderton, Mark;Wrigley, Gail L.
通讯作者：
Wrigley, Gail L.
影响因子：
3.4
作者：
Kalyukina, Maria;Yosaatmadja, Yuliana;Squire, Christopher J.
通讯作者：
Squire, Christopher J.
影响因子：
51.1
作者：
Miller, Vincent A.;Hirsh, Vera;Yang, James Chih-Hsin
通讯作者：
Yang, James Chih-Hsin
影响因子：
7.3
作者：
Guagnano, Vito;Furet, Pascal;Porta, Diana Graus
通讯作者：
Porta, Diana Graus