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Article

7-Aminoalkoxy-Quinazolines from Epigenetic Focused Libraries Are Potent and Selective Inhibitors of DNA Methyltransferase 1

1
DIFACQUIM Research Group, Department of Pharmacy, School of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico
2
Department of Pharmacology, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV), Mexico City 07360, Mexico
*
Author to whom correspondence should be addressed.
Academic Editors: Paola Arimondo and Frank J. Dekker
Molecules 2022, 27(9), 2892; https://doi.org/10.3390/molecules27092892
Received: 10 April 2022 / Revised: 24 April 2022 / Accepted: 30 April 2022 / Published: 30 April 2022
(This article belongs to the Special Issue Drug Discovery and Development: New Options for Old Diseases)
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. View Full-Text
Keywords: docking; drug discovery; enzyme inhibition; epigenetics; epi-informatics; focused library; molecular dynamics; multi-target epigenetic agent; polypharmacology; quinazoline docking; drug discovery; enzyme inhibition; epigenetics; epi-informatics; focused library; molecular dynamics; multi-target epigenetic agent; polypharmacology; quinazoline
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MDPI and ACS Style

Medina-Franco, J.L.; López-López, E.; Martínez-Fernández, L.P. 7-Aminoalkoxy-Quinazolines from Epigenetic Focused Libraries Are Potent and Selective Inhibitors of DNA Methyltransferase 1. Molecules 2022, 27, 2892. https://doi.org/10.3390/molecules27092892

AMA Style

Medina-Franco JL, López-López E, Martínez-Fernández LP. 7-Aminoalkoxy-Quinazolines from Epigenetic Focused Libraries Are Potent and Selective Inhibitors of DNA Methyltransferase 1. Molecules. 2022; 27(9):2892. https://doi.org/10.3390/molecules27092892

Chicago/Turabian Style

Medina-Franco, José L., Edgar López-López, and Liliam P. Martínez-Fernández. 2022. "7-Aminoalkoxy-Quinazolines from Epigenetic Focused Libraries Are Potent and Selective Inhibitors of DNA Methyltransferase 1" Molecules 27, no. 9: 2892. https://doi.org/10.3390/molecules27092892

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