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

08 March 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Inhibitors of epigenetic writers such as DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug and probe discovery. There are many small molecules tested as inhibitors of DNMTs but, overall, they do not have potent enzymatic inhibition. Chemical companies are developing focused libraries for epigenetic targets to advance probe and drug discovery. Based on a knowledge-based approach, herein, we report the identification of two quinazoline-based derivatives identified in focused libraries with nanomolar inhibition of DNMT1 (30 and 81 nM), more potent than the positive control S-adenosylhomocysteine. The two compounds had low micromolar activity of DNMT3A and did not inhibit DNMT3B. The quinazolines reported in this work have low cell toxicity and are potent inhibitors of the epigenetic target writer G9a at the enzymatic and cellular levels. Molecular modeling helped rationalize the enzymatic inhibitory activity at the molecular level of the two compounds against DNMT1 and DNMT3A. The quinazoline-based compounds are attractive as novel potent inhibitors of DNMTs and as dual and selective epigenetic agents targeting two families of epigenetic writers.


drug discovery
enzyme inhibition
focused library
molecular dynamics
multi-target epigenetic agent

Supplementary materials

Supporting information to manuscript "7-Aminoalkoxy-Quinazolines from Epigenetic Focused Libraries are Potent and Selective Inhibitors of DNA Methyltransferase 1"
CONTENTS: Table S1: Results of the relative enzymatic activity of DNMT1 as percentages; Table S2: Results of dose-response evaluations for selected quinazolines (IC50) with DNMT1, DNMT3A, and DNMT3B; Table S3: Number of quinazolines and 7-aminoalkoxy-quinazolines present in commercial epigenetic focused libraries; Figure S1: Molecular dynamic results of S-adenosyl-L-methionine against DNMT1; Figure S2: Conformational changes observed on DNMT1 after the molecular dynamics simulations; Figure S3: In silico profiling of the three compounds with the free online and validate server Epigenetic Target Profiler.


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