Original articles
Xiaowei Wu, Mengdi Dai, Rongrong Cui, Yulan Wang, Chunpu Li, Xia Peng, Jihui Zhao, Bao Wang, Yang Dai, Dan Feng, Tianbiao Yang, Hualiang Jiang, Meiyu Geng, Jing Ai, Mingyue Zheng, Hong Liu. Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 781-794

Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors
Xiaowei Wua, Mengdi Daib,c, Rongrong Cuid, Yulan Wanga, Chunpu Lia, Xia Pengb, Jihui Zhaoa,c, Bao Wanga, Yang Daib, Dan Fenga, Tianbiao Yanga, Hualiang Jianga,d, Meiyu Gengb, Jing Aib,c, Mingyue Zhenga,c,d, Hong Liua
a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
b Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
c University of Chinese Academy of Sciences, Beijing 100049, China;
d School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
Abstract:
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.
Key words:    Tyrosine kinase    Covalent FGFR inhibitors    Virtual screening    Pyrazolo[3,4-d] pyridazinone    Structure—activity relationships    Antitumor efficacy   
Received: 2020-06-02     Revised: 2020-07-23
DOI: 10.1016/j.apsb.2020.09.002
Funds: We gratefully acknowledge financial support from the National Natural Science Foundation of China (81620108027 and 21632008 to Hong Liu, 81773634 to Mingyue Zheng and 81773762 to Jing Ai), National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” (2018ZX09711002, China), the Major Project of Chinese National Programs for Fundamental Research and Development (2015CB910304 to Hong Liu), “Personalized Medicines—Molecular Signature-based Drug Discovery and Development”, and Strategic Priority Research Pro-gram of the Chinese Academy of Sciences (XDA12050201 to Mingyue Zheng, XDA12020000 to Meiyu Geng and XDA12020103 to Jing Ai). The Natural Science Foundation of China for Innovation Research Group (81821005 to Meiyu Geng, China). The Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning (2020CXJQ02 to Meiyu Geng, China).
Corresponding author: Jing Ai, Mingyue Zheng, Hong Liu     Email:jai@simm.ac.cn;myzheng@simm.ac.cn;hliu@simm.ac.cn
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Xiaowei Wu
Mengdi Dai
Rongrong Cui
Yulan Wang
Chunpu Li
Xia Peng
Jihui Zhao
Bao Wang
Yang Dai
Dan Feng
Tianbiao Yang
Hualiang Jiang
Meiyu Geng
Jing Ai
Mingyue Zheng
Hong Liu

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