Final Report Summary - DEKKER40 (Novel approaches towards understanding of gene transcription using small molecules as tools)
The quickly increasing understanding of the epigenetic regulation of gene transcription indicates that enzymes that are involved in these processes are potential drug targets. Histone acetyltransferases are a newly discovered class of enzymes for which no potent and selective inhibitors have been described so far. Nevertheless, basic science as well as drug discovery efforts in pharmaceutical companies will benefit from the development of potent and selective small molecules inhibitors for these enzymes.
We studied the HAT inhibitors called isothiazolone extensively and found that these compounds bind chemoselectively to thiolates. We studied specificity for inhibition of the thiolate dependent histone acetyltransferase PCAF in comparison with the thiolate dependent protease cathepsin B. We observed specificity for several inhibitors for inhibition of both enzymes. This property is beneficial for the development of probes for so-called activity-based profiling of these enzymes. In this approach the inhibitors are used as probes to identify active enzymes in different tissues. Ultimately, this will result in identification of disease related histone acetyltransferases.
We studied a series of non-covalent inhibitors of histone acetyltransferases that were based on the natural product anacardic acid. A focussed compound collection was synthesized and screened for inhibition of three different histone acetyltransferases. Inhibitors with improved potency and selectivity were identifed.
Furthermore, an inhibitors was identfied with improved potency in cell-based studies on inhibition of histone acetylation. The most promising molecules are currently under investigation in disease models for inflammatory diseases like for example asthma. The inhibitors are able to inhibit NFkappaB mediated gene transcription and the release of inflammatory mediated such as interleukin 8 upon stimulation of epithelials cells with TNFalpha. These results indacte that anacardic acid derived inhibitors are promising candicated for further investigations towards treatement of inflammatory diseases.
We studied the HAT inhibitors called isothiazolone extensively and found that these compounds bind chemoselectively to thiolates. We studied specificity for inhibition of the thiolate dependent histone acetyltransferase PCAF in comparison with the thiolate dependent protease cathepsin B. We observed specificity for several inhibitors for inhibition of both enzymes. This property is beneficial for the development of probes for so-called activity-based profiling of these enzymes. In this approach the inhibitors are used as probes to identify active enzymes in different tissues. Ultimately, this will result in identification of disease related histone acetyltransferases.
We studied a series of non-covalent inhibitors of histone acetyltransferases that were based on the natural product anacardic acid. A focussed compound collection was synthesized and screened for inhibition of three different histone acetyltransferases. Inhibitors with improved potency and selectivity were identifed.
Furthermore, an inhibitors was identfied with improved potency in cell-based studies on inhibition of histone acetylation. The most promising molecules are currently under investigation in disease models for inflammatory diseases like for example asthma. The inhibitors are able to inhibit NFkappaB mediated gene transcription and the release of inflammatory mediated such as interleukin 8 upon stimulation of epithelials cells with TNFalpha. These results indacte that anacardic acid derived inhibitors are promising candicated for further investigations towards treatement of inflammatory diseases.