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 alre...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 14 q was finally identified to repress LSD1 with IC50=183 nmol/L.Docking analysis suggested that compound 14 q fitted well into the FAD-binding pocket.Further mechanism studies showed that compound 14 q 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 compound14 q is a suitable candidate for further development of novel FAD similarity-based LSD1 inhibitors.展开更多
基金supported by National Natural Science Foundation of China(Project Nos.81430085 and 81773562 for Hongmin Liu,No.81602961 for Yichao Zheng and No.81703328 for Liying Ma)National Key Research Program(Nos.2018YFE0195100 and 2016YFA0501800 for Hongmin Liu,China)+1 种基金Science and Technology Innovation Talents of Henan Provincial Education Department(19IRTSTHN001,China)Scientific Program of Henan Province(No.182102310070,for Liying Ma,China)
文摘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 14 q was finally identified to repress LSD1 with IC50=183 nmol/L.Docking analysis suggested that compound 14 q fitted well into the FAD-binding pocket.Further mechanism studies showed that compound 14 q 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 compound14 q is a suitable candidate for further development of novel FAD similarity-based LSD1 inhibitors.
