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Pyrido- and Benzisothiazolones as Inhibitors of Histone Acetyltransferases (HATs)

Silviya Dimitrova FurdasInga HoffmannDina RobaaManfred Jung

出版	Albert-Ludwigs-Universität Freiburg, 2014
URL	http://books.google.com.hk/books?id=RPB-swEACAAJ&hl=&source=gbs_api

註釋Abstract: 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