The initial enthusiasm following the discovery of a pharmacologically active
natural product is often fleeting due to the poor prospects for its ultimate clinical application. Despite this, the ever-changing landscape of modern biology has a constant need for
molecular probes that can aid in our understanding of biological processes. After its initial discovery by Bristol-Myers Squibb as a microbial anti-
tumor natural product,
epoxomicin was deemed unfit for development due to its
peptide structure and potentially labile epoxyketone pharmacophore. Despite its drawbacks,
epoxomicin's pharmacophore was found to provide unprecedented selectivity for the
proteasome.
Epoxomicin also served as a scaffold for the generation of a synthetic tetrapeptide epoxyketone with improved activity, YU-101, which became the parent lead compound of
carfilzomib (Kyprolis™), the recently approved therapeutic agent for
multiple myeloma. In this era of rational
drug design and high-throughput screening, the prospects for turning an active
natural product into an approved
therapy are often slim. However, by understanding the journey that began with the discovery of
epoxomicin and ended with the successful use of
carfilzomib in the clinic, we may find new insights into the keys for success in
natural product-based
drug discovery.