Olaf Wiest’s laboratory has developed structural models for the different human histone deacetylases (HDACs) that can enable the identification of HDAC inhibitors (HDACi) that are to distinguish them. The research aims to overcome the major problem that hampers use of the promising HDAC inhibitors in fighting cancer. So far, they inhibit most or all of the 18 HDAC isoforms present in humans, leading to such side effects as cardiotoxicity or fatigue.

The laboratory’s models have been exploited to design novel, potent, and selective HDAC, which have been synthesized and tested in collaborations with synthetic chemists and biochemists. Researchers were able to achieve high selectivity for the inhibitors. The laboratory also has designed several metal binders of similar potency but higher selectivity than hydroxamates. Together, these studies can lead to the design of tailor-made HDACi for each individual isoform that can serve as drug leads or biochemical tool compounds in a variety of cancer studies. The discoveries also could help decipher the cellular and molecular processes connecting gene transcription to cancer and other diseases.