Identification of selective inhibitors of NAD+-dependent deacetylases using phenotypic screens in yeast.


Sir2 and Hst1 are NAD+-dependent deacetylases involved in transcriptional repression in yeast. The two enzymes are highly homologous yet have different sensitivity to the small-molecule inhibitor splitomicin (compound 1) (Bedalov, A., Gatbonton, T., Irvine, W. P., Gottschling, D. E., and Simon, J. A. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 15113-15118). We have now defined a critical amino acid residue within a small helical module of Hst1 that confers relative resistance to splitomicin. Parallel cell-based screens of 100 splitomicin analogues led to the identification of compounds that exhibit a higher degree of selectivity toward Sir2 or Hst1. A series of compounds based on a splitomicin derivative, dehydrosplitomicin (compound 2), effectively phenocopied a yeast strain that lacked Hst1 deacetylase while having no effect on the silencing activities of Sir2. In addition, we identified a compound with improved selectivity for Sir2. Selectivity was affirmed using whole-genome DNA microarray analysis. This study underscores the power of phenotypic screens in the development and characterization of selective inhibitors of enzyme functions.


Citations per Year

371 Citations

Semantic Scholar estimates that this publication has 371 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Hirao2003IdentificationOS, title={Identification of selective inhibitors of NAD+-dependent deacetylases using phenotypic screens in yeast.}, author={Maki Hirao and Jeffrey Posakony and Melisa Nelson and Henning Hruby and Manfred Jung and Julian A Simon and Antonio Bedalov}, journal={The Journal of biological chemistry}, year={2003}, volume={278 52}, pages={52773-82} }