HATs off: Selective synthetic inhibitors of the histone acetyltransferasesp300 and PCAF

Histone acetyltransferases (HATs) play important roles in the regulation of gene expression. In this report, we describe the design, synthesis, and ap plication of peptide CoA conjugates as selective HAT inhibitors for the tra nscriptional coactivators p300 and PCAF. Two inhibitors (Lys-CoA for p300 a nd H3-CoA-20 for PCAF) were found to be potent (IC50 approximate to 0.5 mu M) and selective (similar to 200-fold) in blocking p300 and PCAF HAT activi ties. These inhibitors were used to probe enzymatic and transcriptional fea tures of HAT function in several assay systems. These compounds should be b roadly useful as biological tools for evaluating the roles of HATs in trans criptional studies and may serve as lead agents for the development of nove l antineoplastic therapeutics.