title: Design, synthesis and biological evaluation of [1,2,4]triazolo[1,5-a]pyrimidines as potent lysine specific demethylase 1 (LSD1/KDM1A) inhibitors.
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.
authors: School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.
authors: Shuai
authors: S
authors: Wang
authors: School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.
authors: Li-Jie
authors: LJ
authors: Zhao
authors: School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.
authors: Yi-Chao
authors: YC
authors: Zheng
authors: School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.
authors: Dan-Dan
authors: DD
authors: Shen
authors: School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.
authors: Er-Fei
authors: EF
authors: Miao
authors: School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.
authors: Xue-Peng
authors: XP
authors: Qiao
authors: School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.
authors: Li-Juan
authors: LJ
authors: Zhao
authors: School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.
authors: Ying
authors: Y
authors: Liu
authors: School of Pharmaceutical Sciences, Central South University, Changsha 410000, China.
authors: Ruilei
authors: R
authors: Huang
authors: School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China. Electronic address: zzuyubin@hotmail.com.
authors: Bin
authors: B
authors: Yu
authors: 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.
authors: Hong-Min
authors: HM
authors: Liu
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: Cytotoxicity; Docking studies; LSD1 inactivation; Migration inhibition; [1,2,4]triazolo[1,5-a]pyrimidine