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

Autor: Ma L; 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., Wang H; 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., You Y; 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., Ma C; 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., Liu Y; 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., Yang F; 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., Zheng Y; 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., Liu H; 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.
Jazyk: angličtina
Zdroj: Acta pharmaceutica Sinica. B [Acta Pharm Sin B] 2020 Sep; Vol. 10 (9), pp. 1658-1668. Date of Electronic Publication: 2020 Feb 24.
DOI: 10.1016/j.apsb.2020.02.006
Abstrakt: 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 IC 50  = 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.
(© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)
Databáze: MEDLINE
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