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Issue 5, 2013
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From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes

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Covering: 1992 to 2012

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.

Graphical abstract: From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes

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Publication details

The article was received on 29 Dec 2012 and first published on 11 Apr 2013

Article type: Highlight
DOI: 10.1039/C3NP20126K
Nat. Prod. Rep., 2013,30, 600-604

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    From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes

    K. B. Kim and C. M. Crews, Nat. Prod. Rep., 2013, 30, 600
    DOI: 10.1039/C3NP20126K

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