Epothilones: novel microtubule-stabilising agents.
The past few years have witnessed the regulatory approvals of the anticancer microtubule stabilising taxane drugs, Taxol and Taxotere, which are rapidly gaining acceptance as important antineoplastic agents with potential against numerous solid tumour malignancies. Despite a basic understanding of the biochemical target of taxanes dating back nearly 20 years, new classes of tubulin-binding microtubule polymerisation enhancers were only reported in the last two years. Epothilones and discodermolide are newly discovered compounds, which are structurally distinct from the taxanes, but which possess similar tubulin polymerising and cell biological effects. In the first studies reported, these compounds displayed similar or greater potencies than taxanes, and the epothilones may represent an advance over the taxanes in retaining toxicity against various taxane-resistant cell lines. This review summarises the data published on epothilones and discodermolide and proposes further steps that could establish these new classes of compounds as potential second generation microtubule polymerisation enhancers.
Bollag
D M
DM
Merck Research Laboratories, West Point, PA 19486, USA.