Abstract B193: Identification of selective inhibitors of ubiquitin specific proteases

Regulated protein turnover is primarily controlled by the ubiquitin‐proteasome system. The therapeutic efficacy of the proteasome inhibitor Bortezomib establishes this system as a valid anticancer therapeutic field. A promising alternative to targeting the proteasome itself lies upstream, at the level of the ubiquitin conjugation/deconjugation step to generate more specific anticancer agents. Ubiquitin‐specific proteases (USP) are involved in the deubiquitination of specific target substrates regulating their stability, subcellular localization and/or activation status. USP represent a druggable target class due to their thiol‐protease catalytic core which is amenable to pharmacological inhibition by small molecules. A genome‐wide RNAi screen of the catalytically active human USPs in cancer‐relevant cellular models and phenotypic assays allowed us to identify USP7/HAUSP and USP8/UBPY as promising cancer targets. Fluorescence‐based screening assays using optimized USP substrates including various ubiquitin derivatives (ubiquitin precursor, branched ubiquitin chains) as well as specific, physiological substrates were developed. High‐throughput screening performed on our chemically diverse library followed by different optimization programs resulted in the discovery of several series as novel USP inhibitors. Our progress made towards the specificity issue will be presented here with the identification of the first USP8‐ and USP7‐specific series. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B193.