1. [1,2,3]Triazolo[4,5-d]pyrimidine derivatives incorporating (thio)urea moiety as a novel scaffold for LSD1 inhibitors.
- Author
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Li ZH, Ma JL, Liu GZ, Zhang XH, Qin TT, Ren WH, Zhao TQ, Chen XH, and Zhang ZQ
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Histone Demethylases metabolism, Humans, Molecular Docking Simulation, Molecular Structure, Pyrimidines chemical synthesis, Pyrimidines chemistry, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles chemistry, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Histone Demethylases antagonists & inhibitors, Pyrimidines pharmacology, Triazoles pharmacology
- 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., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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