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SUMMARY:Design and use of chemical tools to modulate gene expression in ca
 ncer cells based on the targeting of DNA methyltransferase - Paola B. Arim
 ondo\, CNRS Pierre Fabre Laboratories\, Toulouse France Oversea Fellow Chu
 rchill College\, Cambridge
DTSTART:20170419T150000Z
DTEND:20170419T160000Z
UID:TALK71461@talks.cam.ac.uk
CONTACT:Jo Lockhart
DESCRIPTION:DNA methylation is involved in the regulation of gene expressi
 on and plays an important role in normal developmental processes and disea
 se. In particular\, the epigenetic landscape is altered in cancers where a
 bnormal hypermethylation leads to silencing of certain genes such as tumor
  suppressor genes. In mammals\, DNA methyltransferases are the enzymes res
 ponsible for DNA methylation on the position 5 of cytidine in a CpG contex
 t. Few direct enzyme inhibitors are known and those have several drawbacks
 . In order to identify novel inhibitors\, we developed three chemical stra
 tegies. First a fluorescent High-Throughput Screening for the inhibition o
 f the murine catalytic Dnmt3a/3L complex on the chemical library of the Mu
 séum Naturelle d’Histoire Naturelle and found twelve hits with low micr
 omolar activities. Two molecules efficiently reactivated YFP gene expressi
 on in a stable HEK293 cell line by promoter demethylation. Second\, based 
 on molecular modeling studies of quinoline inhibitor SGI1027\, we synthesi
 zed twenty-five new derivatives. Four compounds induced the reexpression o
 f a reporter gene\, controlled by a methylated CMV promoter\, in leukemia 
 KG-1 cells. Third\, we carried out a modulation study of the non-nucleosid
 e inhibitor N- Phthaloyl-L-tryptophan or RG108. Two constrained compounds 
 and two NPys derivatives were found at least 10-fold more potent than the 
 reference compound. The cytotoxicity on the tumor DU145 cell line of the m
 ost potent inhibitors was correlated to their inhibitory potency. Finally\
 , docking studies were conducted in order to understand their binding mode
 . The biological activity of the compounds was also addressed in solid and
  hematological cancer cells. Altogether\, these studies provide insights f
 or the design of the next-generation of DNMT inhibitors.
LOCATION:Department of Chemistry (Pfizer lecture theatre)
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