Issue 12, 2014

Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs)


Histone acetyltransferases (HATs) are interesting targets for the treatment of cancer and HIV infections but reports on selective inhibitors are very limited. Here we report structure–activity studies of pyrido- and benzisothiazolones in the in vitro inhibition of histone acetyltransferases, namely PCAF, CBP, Gcn5 and p300 using a heterogeneous assay with antibody mediated quantitation of the acetylation of a peptidic substrate. Dependent on the chemical structure distinct subtype selectivity profiles can be obtained. While N-aryl derivatives usually are rather pan-HAT inhibitors, N-alkyl derivatives show mostly a preference for CBP/p300. Selected compounds were also shown to be inhibitors of MOF. The best inhibitors show submicromolar inhibition of CBP. Selected compounds affect growth of HL-60 leukemic cells and LNCaP prostate carcinoma cells with higher potency on the leukemic cells. Target engagement was shown with reduction of histone acetylation in LNCaP cells.

Graphical abstract: Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs)

Supplementary files

Article information

Article type
Concise Article
10 Jun 2014
06 Aug 2014
First published
11 Aug 2014
This article is Open Access
Creative Commons BY license

Med. Chem. Commun., 2014,5, 1856-1862

Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs)

S. D. Furdas, I. Hoffmann, D. Robaa, B. Herquel, W. Malinka, P. Świątek, A. Akhtar, W. Sippl and M. Jung, Med. Chem. Commun., 2014, 5, 1856 DOI: 10.1039/C4MD00245H

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