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Issue 3, 2012
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Rhodanine carboxylic acids as novel inhibitors of histone acetyltransferases

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Abstract

Histone acetyltransferases (HATs) are promising epigenetic drug targets and are involved in the pathogenesis of a wide range of diseases. We carried out a virtual screening based on inhibitors of serotonin N-acetyltransferase and identified novel inhibitors of the HAT PCAF with a 2-thioxo-4-thiazolidinone (rhodanine) scaffold attached to a long chain carboxylic acid. Their binding mode was studied by means of docking and molecular dynamics simulations. Structure–activity studies were performed by organic synthesis and in vitro testing in an antibody based biochemical assay showing similar inhibition on the HATs PCAF, Gcn5, CBP and p300 in vitro. In contrast, a pyridoisothiazolone reference inhibitor is more potent on CBP and to some extent on PCAF but less potent on Gcn5. Structural elements were identified that provide the basis for further optimization of the new inhibitors.

Graphical abstract: Rhodanine carboxylic acids as novel inhibitors of histone acetyltransferases

  • This article is part of the themed collection: Epigenetics
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Publication details

The article was received on 17 Aug 2011, accepted on 09 Jan 2012 and first published on 01 Feb 2012


Article type: Concise Article
DOI: 10.1039/C2MD00211F
Med. Chem. Commun., 2012,3, 305-311

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    Rhodanine carboxylic acids as novel inhibitors of histone acetyltransferases

    S. D. Furdas, S. Shekfeh, S. Kannan, W. Sippl and M. Jung, Med. Chem. Commun., 2012, 3, 305
    DOI: 10.1039/C2MD00211F

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