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Issue 3, 2012
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Rhodaninecarboxylic acids as novel inhibitors of histoneacetyltransferases

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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 HATPCAF 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

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Supplementary files

Article information


Submitted
17 Aug 2011
Accepted
09 Jan 2012
First published
01 Feb 2012

Med. Chem. Commun., 2012,3, 305-311
Article type
Concise Article

Rhodanine carboxylic acids as novel inhibitors of histoneacetyltransferases

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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