Chemical genetics approaches for selective intervention in epigenetics

Andrew C. Runcie, Kwok Ho Chan, Michael Zengerle, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalReview article

15 Citations (Scopus)
175 Downloads (Pure)

Abstract

Chemical genetics is the use of biologically active small molecules (chemical probes) to investigate the functions of gene products, through the modulation of protein activity. Recent years have seen significant progress in the application of chemical genetics to study epigenetics, following the development of new chemical probes, a growing appreciation of the role of epigenetics in disease and a recognition of the need and utility of high-quality, cell-active chemical probes. In this review, we single out the bromodomain reader domains as a prime example of both the success, and challenges facing chemical genetics. The difficulty in generating single-target selectivity has long been a thorn in the side of chemical genetics, however, recent developments in advanced forms of chemical genetics promise to bypass this, and other, limitations. The ‘bump-and-hole’ approach has now been used to probe — for the first time — the BET bromodomain subfamily with single-target selectivity and may be applicable to other epigenetic domains. Meanwhile, PROTAC compounds have been shown to be significantly more efficacious than standard domain inhibitors, and have the potential to enhance target selectivity.

Original languageEnglish
Pages (from-to)186-194
Number of pages9
JournalCurrent Opinion in Chemical Biology
Volume33
Early online date14 Jul 2016
DOIs
Publication statusPublished - Aug 2016

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    A ‘bump-&-hole’ approach for engineering allele-selective inhibition of the BET bromodomains

    Author: Runcie, A. C., 2019

    Supervisor: Ciulli, A. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy

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