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Divalent tranylcypromine derivative as lysine-specific demethylase 1 inhibitor

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Abstract

Tranylcypromine (TCP) is a useful pharmacophore for lysine-specific demethylase 1 (LSD1) inhibitors. Based on the mode of action (MOA) of TCP and structure of LSD1, divalent TCP derivatives with aliphatic and benzylic linkers were designed, synthesized, and evaluated for their LSD1 inhibitory activity, MV4-11 antiproliferative activity, and CD86 mRNA expression enhancement. All ten new compounds showed improved activity against LSD1 than TCP and GSK2879552. Several compounds with rigid aliphatic linkers demonstrated nanomolar enzymatic and cellular activities, as well as good MAO-A/B selectivity. Further supported by their significant CD86 mRNA expression enhancement effect, divalent TCP derivative can be promising lead for new LSD1 inhibitors.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (21877121, 81673309, and 81703544) and China Postdoctoral Science Foundation (2019M661671), the program for Innovative Research Team of the Ministry of Education, and program for Liaoning Innovative Research Team at Shenyang Pharmaceutical University.

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Author notes

  1. These authors contributed equally: Yin Sun, Na Li

Authors and Affiliations

  1. Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Lu, 110016, Shenyang, PR China

    Yin Sun & Dongmei Zhao

  2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, PR China

    Yin Sun, Na Li, Xiaowen Wang, Bing Xiong, Tongchao Liu & Yue-Lei Chen

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

    Na Li, Mingbo Su, Bing Xiong, Yubo Zhou & Yue-Lei Chen

  4. The National Center for Drug Screening, 189 Guoshoujing Road, 201203, Shanghai, PR China

    Mingbo Su & Yubo Zhou

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  1. Yin Sun
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  2. Na Li
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  3. Mingbo Su
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Correspondence to Dongmei Zhao, Yubo Zhou or Tongchao Liu.

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This study is dedicated to Prof. Dr. Robert Vince on the occasion of his 80th birthday.

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Sun, Y., Li, N., Su, M. et al. Divalent tranylcypromine derivative as lysine-specific demethylase 1 inhibitor. Med Chem Res 30, 421–428 (2021). https://doi.org/10.1007/s00044-020-02689-z

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  • DOI: https://doi.org/10.1007/s00044-020-02689-z

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