Previously, we utilized phenotypic, cell-based screening to identify BRD0476 as a complex small molecule that inhibits cytokine-induced apoptosis of pancreatic beta-cells, a model for type-1 diabetes. Here, we describe mechanism-of-action studies that elucidated the deubiquitinase Usp9x as the cellular target of BRD0476. Ubiquitination is a reversible post-translational protein modification with roles in signal transduction and protein degradation. Deubiquitinases (DUBs), proteases that reverse this process, are emerging targets for small-molecule inhibition to regulate protein function in diseases. Using BRD0476 and analogs, we have uncovered regulatory roles for Usp9x in JAK-STAT signaling and validated that inhibition of Usp9x promotes downregulation of the oncogene Mcl-1 through the ubiquitin-proteasome system. Leveraging these successes, we have initiated studies to screen for additional modulators of Usp9x using small-molecule microarrays (SMMs), which may lead to the identification of new lead compounds for the treatment of type-1 diabetes and cancer.

Small-molecule modulators of the deubiquitinase Usp9x

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.