Document Detail

Identification of Novel Inhibitors of DNA methylation by Screening of a Chemical Library.
MedLine Citation:
PMID:  23294304     Owner:  NLM     Status:  Publisher    
In order to discover new inhibitors of the DNA methyltransferase 3A/3L complex, we used a medium-throughput non-radioactive screen on a random collection of 1120 small organic compounds. After a primary hit detection against DNA methylation activity of the murine Dnmt3A/3L catalytic complex, we further evaluated the EC50 of the twelve most potent hits as well as their cytotoxicity on DU145 prostate cancer cultured cells. Interestingly, most of the inhibitors showed low micromolar activities and little cytotoxicity. Dichlone, a small halogenated naphthoquinone, classically used as pesticide and fungicide, showed the lowest EC50 at 460 nM. We briefly assessed the selectivity of a subset of our new inhibitors against hDNMT1 and bacterial DNMTs, including M.SssI and EcoDam, and the protein lysine methyltransferase PKMT G9a and the mode of inhibition. Globally, the tested molecules showed a clear preference for the DNA methyltransferases, but poor selectivity among them. Two molecules including Dichlone, efficiently reactivated YFP gene expression in a stable HEK293 cell line by promoter demethylation. Their efficacy was comparable to the DNMT inhibitor of reference 5-azacytidine.
Alexandre Ceccaldi; Arumugam Rajavelu; Sergey Ragozin; Catherine Sénamaud-Beaufort; Pavel Bashtrykov; Noé Testa; Hana Dali-Ali; Christine Maulay-Bailly; Severine Amand; Dominique Guianvarc'h; Albert Jeltsch; Paola B Arimondo
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-8
Journal Detail:
Title:  ACS chemical biology     Volume:  -     ISSN:  1554-8937     ISO Abbreviation:  ACS Chem. Biol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101282906     Medline TA:  ACS Chem Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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