2. Academic Validation
  3. Discovery of novel tranylcypromine-based derivatives as LSD1 inhibitors for gastric cancer treatment

Discovery of novel tranylcypromine-based derivatives as LSD1 inhibitors for gastric cancer treatment

  • Eur J Med Chem. 2023 May 5;251:115228. doi: 10.1016/j.ejmech.2023.115228.
Qi-Sheng Ma 1,  Yi-Fan Zhang 1,  Cheng-Yang Li 2,  Wei-Xin Zhang 1,  Lu Yuan 3,  Jin-Bo Niu 4,  Jian Song 5,  Sai-Yang Zhang 6,  Hong-Min Liu 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
  • 2 Luohe Food Vocationl College, Luohe, 462333, China.
  • 3 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 4 The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • 5 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
  • 6 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
  • 7 School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
PMID: 36881982 DOI: 10.1016/j.ejmech.2023.115228
Abstract

As an important epigenetic regulator, histone lysine specific demethylase 1 (LSD1) has become an attractive target for the discovery of Anticancer agents. In this work, a series of tranylcypromine-based derivatives were designed and synthesized. Among them, compound 12u exhibited the most potent inhibitory potency on LSD1 (IC50 = 25.3 nM), and also displayed good antiproliferative effects on MGC-803, KYSE450 and HCT-116 cells with IC50 values of 14.3, 22.8 and 16.3 μM, respectively. Further studies revealed that compound 12u could directly act on LSD1 and inhibit LSD1 in MGC-803 cells, thereby significantly increasing the expression levels of mono-/bi-methylation of H3K4 and H3K9. In addition, compound 12u could induce Apoptosis and differentiation, inhibit migration and cell stemness in MGC-803 cells. All these findings suggested that compound 12u was an active tranylcypromine-based derivative as a LSD1 inhibitor that inhibited gastric Cancer.

Keywords

Antiproliferative activities; LSD1; Tranylcypromine.

Figures
Products