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Discovery and Development of the Epothilones

A Novel Class of Antineoplastic Drugs

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Abstract

The epothilones are a novel class of antineoplastic agents possessing antitubulin activity. The compounds were originally identified as secondary metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum. Two major compounds, epothilone A and epothilone B, were purified from the S. cellulosum strain So ce90 and their structures were identified as 16-member macrolides. Initial screening with these compounds revealed a very narrow and selective antifungal activity against the zygomycete, Mucor hiemalis. In addition, strong cytotoxic activity against eukaryotic cells, mouse L929 fibroblasts and human T-24 bladder carcinoma cells was observed. Subsequent studies revealed that epothilones induce tubulin polymerization and enhance microtubule stability. Epothilone-induced stabilisation of microtubules was shown to cause arrest at the G2/M transition of the cell cycle and apoptosis. The compounds are active against cancer cells that have developed resistance to taxanes as a result of acquisition of β-tubulin overexpression or mutations and against multidrug-resistant cells that overexpress P-glycoprotein or multidrug resistance-associated protein. Thus, epothilones represent a new class of antimicrotubule agents with low susceptibility to key tumour resistance mechanisms.

More recently, a range of synthetic and semisynthetic epothilone analogues have been produced to further improve the adverse effect profile (or therapeutic window) and to maximize pharmacokinetic and antitumour properties. Various epothilone analogues have demonstrated activity against many tumour types in preclinical studies and several compounds have been and still are being evaluated in clinical trials. This article reviews the identification and early molecular characterization of the epothilones, which has provided insight into the mode of action of these novel antitumour agents in vivo.

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Acknowledgements

Research work related to this manuscript was supported by the Helmholtz Centre for Infection Research. The authors gratefully acknowledge the editorial assistance of Roy Garcia, PhD in the preparation of this article and thank Bristol-Myers Squibb for their support in providing access to information on ixabepilone. The authors are consultants for Bristol-Myers Squibb.

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  1. Helmholtz-Zentrum für Infektionsforschung, Inhoffenstr. 7, Braunschweig, D-38124, Germany

    Hans Reichenbach & Gerhard Höfle

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  1. Hans Reichenbach
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  2. Gerhard Höfle
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Correspondence to Hans Reichenbach.

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Formerly Gesellschaft für Biotechnologische Forschung (GBF) [Department of Natural Products].

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Reichenbach, H., Höfle, G. Discovery and Development of the Epothilones. Drugs R D 9, 1–10 (2008). https://doi.org/10.2165/00126839-200809010-00001

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