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Synthesis of triazolotriazine derivatives as c-Met inhibitors

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Abstract

Receptor tyrosine kinase c-Met is an important antitumor drug target. Triazolotriazine analogues 2–10 were prepared efficiently and evaluated the enzymatic and cellular c-Met activities. Brief structure–activity relationships of triazolotriazine core and CF2-quinoline part were investigated, leading to the discovery of compound 8 with nanomolar enzymatic c-Met activity, and subnanomolar MKN45 and EBC-1 cellular potencies. The proposed binding model of 8 and c-Met unraveled that two canonical hydrogen bonds and a π–π stacking interaction formed between the inhibitor and the ATP binding site of c-Met kinase domain, which accounted for its potent c-Met activities.

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Acknowledgements

We thank Shanghai Sailing Program (No. 17YF1423300), the Youth Innovation Promotion Association of CAS (No. 2018324), National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (No. 2018ZX09711002-011-016), “Strategic Priority Research Program” of the Chinese Academy of Sciences (No. XDA12020228), and the National Natural Science Foundation of China (No. 21702220) for their financial support.

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  1. Yuting Guo and Xia Peng have contributed equally to this work.

Authors and Affiliations

  1. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China

    Yuting Guo, Zhengsheng Zhan & Wenhu Duan

  2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China

    Xia Peng, Yinchun Ji, Yitong Zhang, Jian Ding & Jing Ai

  3. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China

    Yuting Guo, Yitong Zhang, Jian Ding, Jing Ai & Wenhu Duan

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  1. Yuting Guo
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  2. Xia Peng
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  3. Yinchun Ji
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Correspondence to Zhengsheng Zhan, Jing Ai or Wenhu Duan.

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Guo, Y., Peng, X., Ji, Y. et al. Synthesis of triazolotriazine derivatives as c-Met inhibitors. Mol Divers 25, 839–846 (2021). https://doi.org/10.1007/s11030-020-10067-5

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