1. Academic Validation
  2. Detailed Exploration around 4-Aminoquinolines Chemical Space to Navigate the Lysine Methyltransferase G9a and DNA Methyltransferase Biological Spaces

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

  • J Med Chem. 2018 Aug 9;61(15):6546-6573. doi: 10.1021/acs.jmedchem.7b01925.
Obdulia Rabal Juan Antonio Sánchez-Arias Edurne San José-Enériz Xabier Agirre Irene de Miguel Leire Garate Estibaliz Miranda Elena Sáez Sergio Roa José Angel Martínez-Climent Yingying Liu 1 Wei Wu 1 Musheng Xu 1 Felipe Prosper 2 Julen Oyarzabal
Affiliations

Affiliations

  • 1 WuXi Apptec (Tianjin) Co. Ltd., TEDA , No. 111 HuangHai Road, Fourth Avenue , Tianjin 300456 , PR China.
  • 2 Departmento de Hematología, Clinica Universidad de Navarra , University of Navarra , Avenida Pio XII 36 , E-31008 Pamplona , Spain.
Abstract

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.

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