Natural Product Inhibitors of the Ubiquitin-Proteasome Pathway

John      S. Schneekloth; Craig      M. Crews

Abstract

Natural products continue to be a source of inspiration for chemists and biologists alike. The search for biologically active natural products has provided troves of information about biological processes, and natural products continue to be some of the most powerful and useful probes of biological processes available. Complex and unusual molecular architectures provide the impetus for new reaction development and push the limits of known synthetic chemistry. In addition to serving as tools for basic research, natural products represent starting points for drug discovery efforts in many cases.

This review details the impressive chemical diversity present in the family of molecules that inhibit the proteasome and other aspects of the ubiquitin-proteasome pathway. To date, over 60 natural products that inhibit the ubiquitin-proteasome pathway have been identified. Although early work recognized inhibitors of the proteasome itself, more modern research has revealed that inhibition of many aspects of this critical pathway is possible. One powerful example of this is the inhibition of the interaction between p53 and MDM2 (an E3 ubiquitin ligase). Natural product proteasome inhibitors have served as powerful tools to unravel the intricacies of the ubiquitin-proteasome and related pathways. Several of these natural products have been developed into anticancer drug candidates, and one proteasome inhibitor has already been approved for the treatment of multiple myeloma. Despite the wealth of information available about naturally occurring proteasome inhibitors and related compounds, it is clear that exciting research about this class of molecules will continue well into the future.

Keywords: Ubiquitin-proteasome pathway, inhibitors, natural products, proteasome, ubiquitin, epoxomicin, lactacystin, salinosporamide, drug discovery, natural product