Epothilones: new tubulin polymerization agents in preclinical and clinical development

The epothilones are tubulin polymerization agents that have recently made their way into clinical development for the treatment of solid tumors. With a mode of action similar to Taxol((R)) and the potential to overcome known mechanisms of drug resistance, these agents may offer advantages over existing therapies. This article describes the discovery of the polyketide-derived epothilone natural products and the ensuing drug discovery efforts to identify improved drug analogues. An overview of the preclinical biological properties of the more promising members of this drug class is provided. Accordingly, the compounds included in this article demonstrate significant in vitro effects on tubulin polymerization and tumor cell viability. In addition, the in vivo activities of 7 different epothilones in human tumor xenograft models has been disclosed and reviewed herein. To date, 2 natural products and 2 semisynthetic analogues have been evaluated in cancer patients (EPO-906, KOS-862, BMS-247550, and BMS-310705), and the preliminary safety and efficacy data from the respective phase I/II studies are discussed.