Christian Olsen

Abstract:

Histone deacetylases (HDACs) are validated targets for treatment of certain cancer types and play numerous regulatory roles in biology, ranging from epigenetics to metabolism. Small molecules are highly important as tool compounds to probe these mechanisms as well as for the development of new medicines. Therefore, detailed mechanistic information and precise characterization of the enzyme substrate preference as well as development of chemical probes to investigate the effects of HDAC enzymes are vital.

Through profiling of both sirtuins and zinc dependent HDACs, we have developed efficient assay formats for inhibitor characterization and discovered enzymatic activities against novel e-N-acyllysine posttranslational modifications, most recently e-N-lactyllysine.

We have interrogated Nature’s arsenal of macrocyclic non-ribosomal peptide HDAC inhibitors by chemical synthesis and evaluation of more than 30 natural products and analogs, which enabled the design of highly potent class I and IIb HDAC inhibitors. We have discovered selective inhibitors of the solo class IV isozyme, HDAC11, by screening of diverse compound collections. Furthermore, our insights into the substrate specificity of sirtuins have been exploited for the design of potent inhibitor tools compounds and photo cross-linking probes against SIRT1–3, 5 and 7. Our work provides novel inhibitors with varying potencies, selectivity profiles, and mechanisms of inhibition, which we hope will help improve interpretation of the function of HDACs and sirtuins in biology and medicine.