Abstract 4043: Characterization of the enzymatic activity, biochemical requirements and inhibition of deubiquitinating enzymes, a novel oncology target class

Abstract

Abstract Deubiquitinating enzymes (DUBs) represent promising opportunities for therapeutic intervention in oncology, and this study reports key information about the catalytic activity, assaying and inhibition of this novel enzyme class. The DUBs are proteases responsible for the cleavage of Ubiquitin from substrate molecules, and the resulting effects on the levels or activity of the substrates has been shown to play key roles in a range of cellular processes. Here we have utilized a range of in vitro and cellular assays of DUB activity to characterize various DUB enzymes, generate high throughput screens and profile DUB inhibition by hit molecules, to further our understanding in this area. The characterization of different DUBs has enabled us to highlight both differences and similarities in their behavior and requirements, particularly with respect to protein subunits, reducing conditions, and activity against different substrates. Profiling of small-molecule hits targeting these enzymes, under various in vitro conditions, and also in a cellular environment, has not only yielded information on the compounds, but has also demonstrated key considerations about the inhibition of these cysteine proteases. Together these findings further our knowledge of this novel target class, as well as providing valuable information to aid the hunt for therapeutic agents modulating these enzymes in a range of oncology settings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4043. doi:10.1158/1538-7445.AM2011-4043