Back to Search
Start Over
Selective Non-nucleoside Inhibitors of Human DNA Methyltransferases Active in Cancer Including in Cancer Stem Cells
- Source :
- Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, American Chemical Society, 2014, 57 (3), pp.701-713. ⟨10.1021/jm4012627⟩, Journal of Medicinal Chemistry; Vol 57
- Publication Year :
- 2014
- Publisher :
- American Chemical Society (ACS), 2014.
-
Abstract
- DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line. © 2014 American Chemical Society.
- Subjects :
- Methyltransferase
Decitabine
Antineoplastic Agents
Pharmacology
Article
Mice
Structure-Activity Relationship
03 medical and health sciences
0302 clinical medicine
Cancer stem cell
Cell Line, Tumor
Drug Discovery
medicine
[CHIM]Chemical Sciences
Animals
Humans
DNA (Cytosine-5-)-Methyltransferases
030304 developmental biology
0303 health sciences
Cell growth
Chemistry
Cancer
medicine.disease
3. Good health
Pyrimidines
Cell culture
030220 oncology & carcinogenesis
Benzamides
Cancer cell
Aminoquinolines
Neoplastic Stem Cells
Quinolines
Molecular Medicine
Drug Screening Assays, Antitumor
Stem cell
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 57
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....00e28e69f185769b4fa323a2b7414a9c