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

Acta Pharmaceutica Sinica B (Sep 2020)

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

Affiliations

Liying Ma: 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
Haojie Wang: 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
Yinghua You: 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
Chaoya Ma: 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
Yuejiao Liu: 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
Feifei Yang: 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
Yichao Zheng: Corresponding authors. Tel./fax: +86 371 67781739.; 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
Hongmin Liu: Corresponding authors. Tel./fax: +86 371 67781739.; 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

Journal volume & issue: Vol. 10, no. 9
pp. 1658 – 1668

Abstract

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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.

Published in Acta Pharmaceutica Sinica B

ISSN: 2211-3835 (Print); 2211-3843 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://www.journals.elsevier.com/acta-pharmaceutica-sinica-b

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