Chemoinformatics contents and chemical diversity analysis of such libraries support their use for drug discovery programs. The most promising DNMTi developed so far are molecules with long scaffolds, for example, the 4aminoquinoline 3 (SGI-027) and its analogs (Figure ). Other quinoline-based derivatives such as compound 8 (CM-272), where the quinoline ring is the main core scaffold (Figure ), have been reported as potent dual inhibitors of DNMT1 and G9a with nanomolar activity. Noteworthy, 8 has remarkable in vivo efficacy (70% tumor growth inhibition of a human acute myeloid leukemia xenograft in a mouse model). The quinolines were developed and further optimized as dual inhibitors based on 7-aminoalkoxy-quinazolines that are inhibitors of G9a such as 12 (MolPort-023-277-153 or UNC0646) and 13 (MolPort-035-789-726 or UNC0631) (Figure ) that are potent inhibitors of G9a in enzymatic and in cellular-based assays. Other quinazoline-based derivatives, for example, 9 (BIX-01294), 10 (UNC-0638), and 11 (UNC-0642) (Figure ) are potent inhibitors of G9a (at the nanomolar level, in particular 10 and 11 (IC 50 <= 55 nM). However, the quinazoline-based derivatives reported so far have low DNMT1 potency (> 2 μM and are mostly inactive, as shown in Figure ). As commented above, DNMTi are emerging as part of programs to develop combination therapies in drug cocktails or compounds targeting multiple epigenetic targets. reported in the literature is included. Chemical content analysis of the novel epigenetic-focused screening libraries (vide supra) revealed that there are several quinazoline-based derivatives similar to 10 (UNC-0638) and 11 (UNC-0642), including two compounds reported in the literature as inhibitors of G9a. Following a knowledge-based approach, i.e. structure-based design reported in the literature and experimental information (vide supra), herein we hypothesized that quinazoline-based derivatives available in the commercial libraries such as 12 and 13 also inhibit the enzymatic activity of DNMTs.