Detailed Exploration around 4‑Aminoquinolines Chemical Space to Navigate the Lysine Methyltransferase G9a and DNA Methyltransferase Biological Spaces

Epigenetic
regulators that exhibit aberrant enzymatic activities or expression
profiles are potential therapeutic targets for cancers. Specifically,
enzymes responsible for methylation at histone-3 lysine-9 (like G9a)
and aberrant DNA hypermethylation (DNMTs) have been implicated in
a number of cancers. Recently, molecules bearing a 4-aminoquinoline
scaffold were reported as dual inhibitors of these targets and showed
a significant in vivo efficacy in animal models of hematological malignancies.
Here, we report a detailed exploration around three growing vectors
born by this chemotype. Exploring this chemical space led to the identification
of features to navigate G9a and DNMT1 biological spaces: not only
their corresponding exclusive areas, selective compounds, but also
common spaces. Thus, we identified from selective G9a and first-in-class
DNMT1 inhibitors, >1 log unit between their IC50 values,
with IC50 < 25 nM (e.g., 43 and 26, respectively) to equipotent inhibitors with IC50 <
50 nM for both targets (e.g., 13). Their ADME/Tox profiling
and antiproliferative efficacies, versus some cancer cell lines, are
also reported.