2. Academic Validation
  3. Design, synthesis and biological evaluation of [1,2,4]triazolo[1,5-a]pyrimidines as potent lysine specific demethylase 1 (LSD1/KDM1A) inhibitors

Design, synthesis and biological evaluation of [1,2,4]triazolo[1,5-a]pyrimidines as potent lysine specific demethylase 1 (LSD1/KDM1A) inhibitors

  • Eur J Med Chem. 2017 Jan 5:125:940-951. doi: 10.1016/j.ejmech.2016.10.021.
Shuai Wang 1,  Li-Jie Zhao 1,  Yi-Chao Zheng 1,  Dan-Dan Shen 1,  Er-Fei Miao 1,  Xue-Peng Qiao 1,  Li-Juan Zhao 1,  Ying Liu 1,  Ruilei Huang 2,  Bin Yu 3,  Hong-Min Liu 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.
  • 2 School of Pharmaceutical Sciences, Central South University, Changsha 410000, China.
  • 3 School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China. Electronic address: zzuyubin@hotmail.com.
  • 4 School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China. Electronic address: liuhm@zzu.edu.cn.
PMID: 27769034 DOI: 10.1016/j.ejmech.2016.10.021
Abstract

A new series of [1,2,4]triazolo[1,5-a]pyrimidine-based LSD1 inhibitors were designed, synthesized, and further evaluated for their cytotoxicity against MGC-803, EC109, A549 and PC-9 cells as well as the ability of inhibiting LSD1. Some of these compounds showed potent inhibition toward LSD1 and selectively inhibited growth of A549 and PC-9 cells. Compound 6l potently inhibited growth of PC-9 cells (IC50 = 0.59 μM), about 4-fold more potent than 5-FU. Further SARs studies led to the identification of compounds 6l-m, which had good growth inhibition against all the tested Cancer cell lines and were much more potent than 5-FU and GSK2879552. Besides, compounds 5p, 5q and 6i inhibited LSD1 potently (IC50 = 0.154, 1.19 and 0.557 μM, respectively). Docking studies revealed that compound 5p formed arene-H interactions with Val333 and hydrogen bonds with surrounding Ala331, Met332, and Ala539 residues. Compound 5p significantly inhibited migration of A549 and PC-9 cells in a concentration-dependent manner, but had different effect on the expression of E-cadherin and N-Cadherin. The [1,2,4]triazolo[1,5-a]pyrimidine scaffold may serve as a starting point for developing potent LSD1 inhibitors for Cancer therapy.

Keywords

Cytotoxicity; Docking studies; LSD1 inactivation; Migration inhibition; [1,2,4]triazolo[1,5-a]pyrimidine.

Figures