The posttranslational conjugation of the Small Ubiquitin-like Modifier (SUMO) to a protein target is a dynamic process that governs many biological processes and disease states.  However, our understanding of protein sumoylation is currently severely limited in part due to a lack of small molecule probes that selectively target the pathway.  Small molecule inhibitors will have substantial value in unraveling the role of SUMO modification in biology, will aid in understanding the mechanism of SUMO conjugating enzymes, and could have potential as anticancer therapeutics.  As part of an effort to identify and study naturally occurring inhibitors of protein sumoylation, our laboratory has developed a novel biochemical microfluidic electrophoretic mobility shift assay.  This assay measures SUMO conjugation to a peptide substrate in an E3 independent fashion.  We have used this assay to identify a mechanistically unique small molecule inhibitor named 2-D08 that blocks SUMO transfer from the E2 thioester to the substrate.  In addition to being the only reported molecule with this mechanism of action, this inhibitor is cell permeable and has unique effects on SUMO-dependent gene expression.  This talk will describe the discovery of 2-D08 as well as recent efforts focused on a high throughput screen of NCI's natural product repository to identify novel inhibitory natural products.

Chemical approaches for studying protein sumoylation

248th National Meeting (2014)

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