Exploration of 5-cyano-6-phenylpyrimidin derivatives containing an 1,2,3-triazole moiety as potent FAD-based LSD1 inhibitors

Liying Ma; Haojie Wang; Yinghua You; Chaoya Ma; Yuejiao Liu; Feifei Yang; Yichao Zheng; Hongmin Liu

doi:10.1016/j.apsb.2020.02.006

Exploration of 5-cyano-6-phenylpyrimidin derivatives containing an 1,2,3-triazole moiety as potent FAD-based LSD1 inhibitors

Acta Pharm Sin B. 2020 Sep;10(9):1658-1668. doi: 10.1016/j.apsb.2020.02.006. Epub 2020 Feb 24.

Authors

Liying Ma¹, Haojie Wang¹, Yinghua You¹, Chaoya Ma¹, Yuejiao Liu¹, Feifei Yang¹, Yichao Zheng¹, Hongmin Liu¹

Affiliation

¹ Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.

Abstract

Histone lysine specific demethylase 1 (LSD1) has become a potential therapeutic target for the treatment of cancer. Discovery and develop novel and potent LSD1 inhibitors is a challenge, although several of them have already entered into clinical trials. Herein, for the first time, we reported the discovery of a series of 5-cyano-6-phenylpyrimidine derivatives as LSD1 inhibitors using flavin adenine dinucleotide (FAD) similarity-based designing strategy, of which compound 14q was finally identified to repress LSD1 with IC₅₀ = 183 nmol/L. Docking analysis suggested that compound 14q fitted well into the FAD-binding pocket. Further mechanism studies showed that compound 14q may inhibit LSD1 activity competitively by occupying the FAD binding sites of LSD1 and inhibit cell migration and invasion by reversing epithelial to mesenchymal transition (EMT). Overall, these findings showed that compound 14q is a suitable candidate for further development of novel FAD similarity-based LSD1 inhibitors.

Keywords: AML, acute myeloid leukemia; ANOVA, analysis of variance; Anticancer; EMT, epithelial to mesenchymal transition; ESI, electrospray ionization; FAD, flavin adenine dinucleotide; FBS, fetal bovine serum; Flavin adenine dinucleotide (FAD); Gastric cancer; HRMS, high resolution mass spectra; IC50, half maximal inhibitory concentration; LSD1 inhibitors; LSD1, histone lysine specific demethylase 1; MOE, molecular operating environment; PAINS, pan assay interference compounds; PDB, the Protein Data Bank; Pyrimidine; RLU, relative light units; SARs, structure–activity relationship studies; TCP, tranylcypromine; VDW, van der Waals.