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Rational design and validation of a Tip60 histone acetyltransferase inhibitor

Journal article
Authors Chunxia Gao
E. Bourke
M. Scobie
M. A. Famme
T. Koolmeister
T. Helleday
Leif A Eriksson
N. F. Lowndes
J. A. L. Brown
Published in Scientific Reports
Volume 4
Pages Article no: 5372
ISSN 2045-2322
Publication year 2014
Published at Department of Chemistry and Molecular Biology
Pages Article no: 5372
Language en
Links dx.doi.org/10.1038/srep05372
Keywords DNA-DAMAGE RESPONSE, CANCER CELL-PROLIFERATION, DOUBLE-STRAND BREAKS, ANDROGEN RECEPTOR, DEACETYLASE INHIBITORS, FORCE-FIELD, ACETYLATION, REPAIR, ATM, ACTIVATION, Multidisciplinary Sciences
Subject categories Microbiology

Abstract

Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer.

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