Ligand-based design, synthesis and biological evaluation of xanthine derivatives as LSD1/KDM1A inhibitors
| Autor: | Junbiao Chang, Hong-Min Liu, Yongfang Yao, Siqi Feng, Bin Yu, Qi-Sheng Ma, Yi-Chao Zheng |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Drug
BRD4 animal structures media_common.quotation_subject Cell Cycle Proteins Ligands 01 natural sciences Cell Line 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Potency Humans Indoleamine-Pyrrole 2 3 -Dioxygenase Epigenetics Enzyme Inhibitors 030304 developmental biology media_common Pharmacology Histone Demethylases 0303 health sciences biology 010405 organic chemistry Chemistry Organic Chemistry Nuclear Proteins KDM1A General Medicine Xanthine Peptide Fragments 0104 chemical sciences Molecular Docking Simulation Histone Biochemistry Docking (molecular) Drug Design Xanthines biology.protein Transcription Factors |
| Zdroj: | European journal of medicinal chemistry. 162 |
| ISSN: | 1768-3254 |
| Popis: | Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for disease treatment. To date, a large number of LSD1 inhibitors have been developed, some of which are currently being evaluated in clinical trials for the treatment of cancers, virus infection, and neurodegenerative diseases. In this paper, we for the first time reported the ligand-based design of fragment-like xanthine derivatives as LSD1 inhibitors, of which compound 4 possessed acceptable pharmacological inhibition against LSD1 (IC50 = 6.45 μM) and favorable fragment-like nature, and therefore could be used as a promising template to design new LSD1 inhibitors. Interestingly, compounds 6c and 6i strongly suppressed growth of MGC-803 cells partly dependent on their LSD1 inhibition, and were also found to be able to inhibit BRD4 and IDO1. The docking studies were performed to rationalize the biochemical potency against LSD1 and to explain the observed activity discrepancy. The proof-of-concept work may provide an example for other natural ligand-based drug design. |
| Databáze: | OpenAIRE |
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