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  current news   Press   selected story    
     
  10 October 2014  
  A Strategy Based on Nucleotide Specificity Leads to Subfamily-Selective and Cell-Active Inhibitor of N6-Methyladenosine Demethylase FTO
 
 




Authors
Joel D. W. Toh#,a,b, Lingyi Sun#,a, Lisa Z. M. Lauha, Jackie Tanc, Joanne J. A. Lowa, Colin W.Q. Tanga, Eleanor J. Y. Cheonga, Melissa J. H. Tana, Yun Chenc,a, WanJin Hongb, Yong-Gui Gao*,b,c and Esther C. Y. Woon*,a

a   Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
b   Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673. 
c    School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore      637551.
#   Contributed equally
*   Joint corresponding authors

Fax: (+65) 6779 1554; Tel: (+65) 6516 2932; E-mail: esther.woon@nus.edu.sg
Fax: (+65) 6779 1117; Tel: (65)6586 9679/6316 2819; Email: ygao@ntu.edu.sg

Published online in Chemical Science on 22 September 2014.

To read the article, please click here: http://pubs.rsc.org/en/Content/ArticleLanding/2014/SC/C4SC02554G#!divAbstract

Abstract

The AlkB family of nucleic acid demethylases is of intense biological and medical interest because of their roles in nucleic acid repair and epigenetic modification. However their functional and molecular mechanisms are unclear, hence, there is strong interest in developing selective inhibitors for them. Here we report the identification of key residues within the nucleotide-binding sites of the AlkB subfamilies that likely determines their substrate specificity. We further provide proof of principle that a strategy exploiting these inherent structural differences can enable selective and potent inhibition of the AlkB subfamilies. This is demonstrated by the first report of a subfamily-selective and cell-active FTO inhibitor 12. The distinct selectivity of 12 for FTO against other AlkB subfamilies and 2OG oxygenases shall be of considerable interest with regards to its potential use as functional probe. The strategy outlined here is likely applicable to other AlkB subfamilies, and, more widely, to other 2OG-oxygenases.

Figure Legend: A selective inhibit bound to the catalytic site of FTO, providing potential application in drug discovery for the anti-obesity crusade.

For more information on Yonggui GAO's laboratory, please click here.
For more information on Wanjin HONG's laboratory, please click here.