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
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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
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.
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.