A novel histone deacetylase inhibitor identified by high-throughput transcriptional screening of a compound library

Libraries of compounds are increasingly becoming commercially available for the use of individual academic laboratories. A high-throughput system base d on a stably integrated transcriptional reporter was used to screen a libr ary of random compounds to identify agents that conferred robust augmentati on of a signal transduction pathway. A novel histone deacetylase (HDAC) inh ibitor, termed scriptaid, conferred the greatest effect, a 12- to 18-fold a ugmentation, This facilitation of transcriptional events was generally appl icable to exogenous gene constructs, including viral and cellular promoters , different cell lines and reporter genes, and stably integrated and transi ently introduced sequences. Scriptaid did not interfere with a further indu ction provided by stimulation of the cognate signal transduction pathway (t ransforming growth factor beta/Smad4), which implied the functional indepen dence of ligand-stimulated transcriptional activation and histone acetylati on states in this system, Additional insights into this and other signal tr ansduction systems are likely to be afforded through the application of com pound screening technologies.