Details

Autor(en) / Beteiligte

• Rabal, Obdulia
• Sánchez-Arias, Juan Antonio
• San José-Enériz, Edurne
• Agirre, Xabier
• de Miguel, Irene
• Garate, Leire
• Miranda, Estibaliz
• Sáez, Elena
• Roa, Sergio
• Martínez-Climent, José Angel
• Liu, Yingying
• Wu, Wei
• Xu, Musheng
• Prosper, Felipe
• Oyarzabal, Julen

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2018-08, Vol.61 (15), p.6546-6573

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.