A Phase 1 STTR proposal seeks to identify and develop novel compounds that target chromatin regulatory proteins. A yeast-based assay will be used to screen the National Cancer Institute Diversity Set library of small molecules. The assay consists of defined yeast mutants or reporter strains whose viability depends on one of a number of chromatin-regulatory functions. Compounds that specifically target those functions cause growth inhibition of the mutant strain but not the corresponding wild-type. There are three parts to the proposal.
In Aim 1, two screens based on novel reporter strains will be carried out with the Diversity Set in order to identify new inhibitors of chromatin function.
In Aim 2, a lead compound from a preliminary screen already conducted wilt be characterized in terms of its effect on histone acetyltransferase activity in vitro and in vivo.
Aim 3 will be devoted to developing a panel of seven yeast and mammalian recombinant HAT enzymes that will be used to test the specific functions of the compounds derived from the screens. The proposed work will contribute to two underdeveloped areas. First it will provide new and valuable reagents for the study of chromatin regulation. With the exception of the histone deacetylase inhibitors (HDACs), drugs that target specific chromatin-related pathways and activities are not available. Second, the preliminary data presented here shows proof-of-concept for the yeast-based technology to rapidly identify chromatin regulation inhibitors. These two areas will be the main thrust of the future development of this project.
