Several groups are working identifying novel potent DNMTi, including dual inhibitors of epigenetic writers such as DNMT and G9a (vide supra). For example, we recently reported DNMT1 inhibitors with novel chemical scaffolds, including two approved for clinical use. However, those compounds lack enough potency (for instance, 4 (glyburide) showed and IC 50 = 55.85 μM using the same assay conditions used in this work). The knowledge of the promising enzymatic and cell-based activity profile of quinoline-based compounds such as 8 (Figure ) as dual inhibitors of DNMT1 and G9a; the high structural similarity of the quinoline-based derivatives to the quinazoline-based derivatives with strong inhibition profile of G9a in enzymatic and cell-based assays; plus the commercial availability of quinazoline-based derivatives in epigenetic focused libraries led us to identify, in this work, the potent and selective inhibition of two 7-aminoalkoxy-quinazolines with 30 and 81 nM potency toward DNMT1 (Figure ). Molecular modeling studies suggest that the selective inhibition of DNMT1 was carried out by the induced conformational change on their CXXC and autoinhibition domains, which is essential for enzymatic activity. Notably, it is reported in the literature that 12 and 13 have high in vitro potency versus G9a (IC 50 = 6 and 4 nM, respectively) and are also highly potent in reducing H3K9me2 levels in human breast adenocarcinoma (MDA-MB-231) cells (26 and 25 nM, respectively) and with low cell toxicity (EC 50 of 3.3 and 2.8 μM, respectively). Potting together, the two 7-aminoalkoxy-quinazolines 12 and 13 are promising compounds to continue developing as polypharmacological, specifically, dual-epigenetic target inhibitors as candidates compounds with potential therapeutic applications.