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

Abstract

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.

Selective degradation of splicing factor CAPERα by anticancer sulfonamides

“…The proteasome inhibitor bortezomib has shown significant efficacy in the treatment of multiple myeloma, and the protein NEDDylation inhibitor MLN4924 is in clinical trials [1][2][3] . Furthermore, the myeloma drug lenalidomide (Supplementary Results, Supplementary Fig.…”

Polymer Micelle Formulations of Proteasome Inhibitor Carfilzomib for Improved Metabolic Stability and Anticancer Efficacy in Human Multiple Myeloma and Lung Cancer Cell Lines

“…To improve upon the success of BTZ, a second-generation, more selective proteasome inhibitor carfilzomib (CFZ; Kyprolis) was approved recently (Arastu-Kapur et al, 2011;Chen et al, 2011). CFZ is a tetrapeptide equipped with an epoxyketone warhead that binds to the active site of the proteasome irreversibly (Kim and Crews, 2013). CFZ has demonstrated efficacy in both BTZ-naive and BTZ-resistant patients and possesses a more favorable toxicity profile compared with BTZ Jakubowiak et al, 2012;Vij et al, 2012).…”

Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration–Approved Drugs

“…Follow-up studies demonstrated profound cytotoxicity and cell cycle block, and the compound was developed by the NCI before approval by the FDA (Piekarz et al, 2001). In the meantime, mechanistic work revealed increased histone acetylation in cells and indicated that the compound acted by inhibiting histone deacetylase (Kim and Crews, 2013). As noted, although phenotypic discovery is mechanism-agnostic, mechanism of action can be determined and provides a basis for future target-based discovery.…”

“…There are many examples of pure phenotypic screening (i.e., in the absence of knowledge about the target) leading to drugs, including the histone deacetylase inhibitors vorinostat (Marks and Breslow, 2007) and romidepsin (Nakajima et al, 1998), and the proteasome inhibitor carfilzomib (Kim and Crews, 2013). Romidepsin (FR901228) was originally isolated and identified as the active constituent of a natural product extract from Chromobacterium violaceum that reversed the cellular morphology of ras-transformed cells (Ueda et al, 1994).…”