2. Academic Validation
  3. [1,2,3]Triazolo[4,5-d]pyrimidine derivatives incorporating (thio)urea moiety as a novel scaffold for LSD1 inhibitors

[1,2,3]Triazolo[4,5-d]pyrimidine derivatives incorporating (thio)urea moiety as a novel scaffold for LSD1 inhibitors

  • Eur J Med Chem. 2020 Feb 1:187:111989. doi: 10.1016/j.ejmech.2019.111989.
Zhong-Hua Li 1,  Jin-Lian Ma 1,  Gai-Zhi Liu 2,  Xin-Hui Zhang 3,  Ting-Ting Qin 1,  Wei-Hong Ren 4,  Tao-Qian Zhao 5,  Xiao-Hui Chen 1,  Zhen-Qiang Zhang 6
Affiliations

Affiliations

  • 1 Scientific Research Center & Laboratory Animal Center, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China.
  • 2 College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China.
  • 3 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China.
  • 4 Department of Laboratory Medicine, The first Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450046, PR China.
  • 5 Department of Chemistry, National University of Singapore, 117543, Singapore.
  • 6 Scientific Research Center & Laboratory Animal Center, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China. Electronic address: zzqkyc@hactcm.edu.cn.
PMID: 31881456 DOI: 10.1016/j.ejmech.2019.111989
Abstract

Lysine specific demethylase 1 (LSD1) plays an essential role in maintaining a balanced methylation status at histone tails. Overexpression of LSD1 has been involved in the development of a variety of human diseases, including cancers. Herein, on the basis of our previously developed LSD1 inhibitors, two series of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives incorporating (thio)urea moiety were designed and evaluated for their LSD1 inhibitory abilities, leading to a novel chemical class of LSD1 inhibitors. Among them, compound 31 was found to moderately inhibit LSD1 activity, as well as increase the expression of H3K4me2 at the cellular level. This compound also showed good selectivity against MAO-A/-B, and a panel of kinases such as CDK and Btk. Besides, the MTT assay suggested that the selected compounds could inhibit the proliferation of LSD1-overexpressed Cancer cells. Although this class of compounds only showed moderate anti-LSD1 activity in the micromolar range, this work presents a novel chemotype of LSD1 inhibitors with good Enzyme selectivity as well as cellular LSD1 inhibitory activity, and could provide a useful template for the development of more potent LSD1 inhibitors for Cancer treatment.

Keywords

(Thio)urea; Antiproliferative activity; Histone demethylase; LSD1; Triazole-pyrimidine.

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