Novel Quinoline Compounds Active in Cancer Cells through Coupled DNA Methyltransferase Inhibition and Degradation
Open Access
- 14 February 2020
- Vol. 12 (2), 447
- https://doi.org/10.3390/cancers12020447
Abstract
DNA methyltransferases (DNMTs) play a relevant role in epigenetic control of cancer cell survival and proliferation. Since only two DNMT inhibitors (azacitidine and decitabine) have been approved to date for the treatment of hematological malignancies, the development of novel potent and specific inhibitors is urgent. Here we describe the design, synthesis, and biological evaluation of a new series of compounds acting at the same time as DNMTs (mainly DNMT3A) inhibitors and degraders. Tested against leukemic and solid cancer cell lines, 2a–c and 4a–c (the last only for leukemias) displayed up to submicromolar antiproliferative activities. In HCT116 cells, such compounds induced EGFP gene expression in a promoter demethylation assay, confirming their demethylating activity in cells. In the same cell line, 2b and 4c chosen as representative samples induced DNMT1 and -3A protein degradation, suggesting for these compounds a double mechanism of DNMT3A inhibition and DNMT protein degradation.Funding Information
- PRIN 2016 (20152TE5PK, PE-2013-02355271, -, -, -, CUP B63D18000560007, -)
- Associazione Italiana per la Ricerca sul Cancro (19162, 17217, 18560)
- National Institutes of Health (R01GM114306)
- FP7 Health (BLUEPRINT - 282510)
This publication has 45 references indexed in Scilit:
- DNA methylation profiles in cancer diagnosis and therapeuticsClinical and Experimental Medicine, 2017
- DNA Methyltransferases Inhibitors from Natural Sources.Current Topics in Medicinal Chemistry, 2015
- DNA methylation inhibitors in cancer: Recent and future approachesBiochimie, 2012
- A decade of exploring the cancer epigenome — biological and translational implicationsNature Reviews Cancer, 2011
- Epigenetic modifications and human diseaseNature Biotechnology, 2010
- Dnmt1/Transcription Factor Interactions: An Alternative Mechanism of DNA Methylation InheritanceGenes & Cancer, 2010
- Dynamic changes in the human methylome during differentiationGenome Research, 2010
- Human DNA methylomes at base resolution show widespread epigenomic differencesNature, 2009
- DNA methylation in cancer: too much, but also too littleOncogene, 2002
- DNA methylation, methyltransferases, and cancerOncogene, 2001