期刊
MOLECULES
卷 27, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/molecules27092892
关键词
docking; drug discovery; enzyme inhibition; epigenetics; epi-informatics; focused library; molecular dynamics; multi-target epigenetic agent; polypharmacology; quinazoline
资金
- Consejo Nacional de Ciencia y Tecnologia (CONACyT), Mexico [762342, CVU: 894234, 1012509]
This study reports two quinazoline-based derivatives with strong inhibitory activity against DNMT1, low affinity for DNMT3A, and no inhibition of DNMT3B. These compounds have low cell toxicity and effectively inhibit G9a.
Inhibitors of epigenetic writers such as DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug and probe discovery. To advance epigenetic probes and drug discovery, chemical companies are developing focused libraries for epigenetic targets. Based on a knowledge-based approach, herein we report the identification of two quinazoline-based derivatives identified in focused libraries with sub-micromolar inhibition of DNMT1 (30 and 81 nM), more potent than S-adenosylhomocysteine. Also, both compounds had a low micromolar affinity of DNMT3A and did not inhibit DNMT3B. The enzymatic inhibitory activity of DNMT1 and DNMT3A was rationalized with molecular modeling. The quinazolines reported in this work are known to have low cell toxicity and be potent inhibitors of the epigenetic target G9a. Therefore, the quinazoline-based compounds presented are attractive not only as novel potent inhibitors of DNMTs but also as dual and selective epigenetic agents targeting two families of epigenetic writers.
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