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Rational Design of Bisubstrate-Type Analogues as Inhibitors of DNA Methyltransferases in Cancer Cells.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2017 Jun 08; Vol. 60 (11), pp. 4665-4679. Date of Electronic Publication: 2017 May 23. - Publication Year :
- 2017
-
Abstract
- Aberrant DNA hypermethylation of promoter of tumor suppressor genes is commonly observed in cancer, and its inhibition by small molecules is promising for their reactivation. Here we designed bisubstrate analogues-based inhibitors, by mimicking each substrate, the S-adenosyl-l-methionine and the deoxycytidine, and linking them together. This approach resulted in quinazoline-quinoline derivatives as potent inhibitors of DNMT3A and DNMT1, some showing certain isoform selectivity. We highlighted the importance of (i) the nature and rigidity of the linker between the two moieties for inhibition, as (ii) the presence of the nitrogen on the quinoline group, and (iii) of a hydrophobic group on the quinazoline. The most potent inhibitors induced demethylation of CDKN2A promoter in colon carcinoma HCT116 cells and its reactivation after 7 days of treatment. Furthermore, in a leukemia cell model system, we found a correlation between demethylation of the promoter induced by the treatment, chromatin opening at the promoter, and the reactivation of a reporter gene.
- Subjects :
- Cell Line, Tumor
DNA (Cytosine-5-)-Methyltransferase 1
DNA Methylation
DNA Methyltransferase 3A
Genes, Tumor Suppressor
Humans
Neoplasms pathology
Substrate Specificity
DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors
Drug Design
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Neoplasms enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 60
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28463515
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.7b00176