Exploration of 5-cyano-6-phenylpyrimidin derivatives containing an 1,2,3-triazole moiety as potent FAD-based LSD1 inhibitors
| Autor: | Yi-Chao Zheng, Yue-Jiao Liu, Li-Ying Ma, Yinghua You, Haojie Wang, Hong-Min Liu, Yang Feifei, Chao-Ya Ma |
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| Rok vydání: | 2020 |
| Předmět: |
MOE
molecular operating environment animal structures 1 2 3-Triazole Pyrimidine Stereochemistry EMT epithelial to mesenchymal transition TCP tranylcypromine IC50 half maximal inhibitory concentration LSD1 histone lysine specific demethylase 1 VDW van der Waals 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine FBS fetal bovine serum PAINS pan assay interference compounds Moiety General Pharmacology Toxicology and Pharmaceutics PDB the Protein Data Bank AML acute myeloid leukemia ANOVA analysis of variance Flavin adenine dinucleotide (FAD) 030304 developmental biology Flavin adenine dinucleotide 0303 health sciences ESI electrospray ionization biology LSD1 inhibitors lcsh:RM1-950 RLU relative light units Cell migration FAD flavin adenine dinucleotide Anticancer lcsh:Therapeutics. Pharmacology Histone HRMS high resolution mass spectra chemistry Docking (molecular) 030220 oncology & carcinogenesis FAD binding biology.protein Original Article SARs structure–activity relationship studies Gastric cancer |
| Zdroj: | Acta Pharmaceutica Sinica B, Vol 10, Iss 9, Pp 1658-1668 (2020) Acta Pharmaceutica Sinica. B |
| ISSN: | 2211-3835 |
| DOI: | 10.1016/j.apsb.2020.02.006 |
| Popis: | 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. Graphical abstract In this work, series II compounds (14a–w) were designed and synthesized based on the flavin adenine dinucleotide (FAD) similarity strategies. Further mechanism studies showed that compound 14q is an FAD competitive LSD1 inhibitor, which inhibits cell migration and invasion by reversing epithelial to mesenchymal transition (EMT).Image 1 |
| Databáze: | OpenAIRE |
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