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Epothilones as lead structures for new anticancer drugs — pharmacology, fermentation, and structure-activity-relationships

  • Chapter
Natural Compounds as Drugs

Part of the book series: Progress in Drug Research ((PDR,volume 66))

Abstract

Epothilones (Epo’s) A and B are naturally occurring microtubule-stabilizers, which inhibit the growth of human cancer cells in vitro at low nM or sub-nM concentrations. In contrast to taxol (paclitaxel, Taxol®) epothilones are also active against different types of multidrug-resistant cancer cell lines in vitro and against multidrug-resistant tumors in vivo. Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and Epo B (EPO906, patupilone) is currently undergoing Phase III clinical trials. Numerous synthetic and semisynthetic analogs have been prepared since the absolute stereochemistry of epothilones was first disclosed in mid-1996 and their in vitro biological activity has been determined. Apart from generating a wealth of SAR information, these efforts have led to the identification of at least six compounds (in addition to Epo B), which are currently at various stages of clinical evaluation in humans. The most advanced of these compounds, Epo B lactam BMS-247550 (ixabepilone), has recently obtained FDA approval for the treatment of metastatic and advanced breast cancer. This chapter will first provide a summary of the basic features of the biological profile of Epo B in vitro and in vivo. This will be followed by a review of the processes that have been developed for the fermentative production of Epo B. The main part of the chapter will focus on the most relevant aspects of the epothilone SAR with regard to effects on tubulin polymerization, in vitro antiproliferative activity, and in vivo antitumor activity. Particular emphasis will be placed on work conducted in the authors’ own laboratories, but data from other groups will also be included. In a final section, the current status of those epothilone analogs undergoing clinical development will be briefly discussed.

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Authors and Affiliations

  1. Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zürich, Switzerland

    Karl-Heinz Altmann

  2. Novartis Institute for Biomedical Research Basel, Switzerland

    Klaus Memmert

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  1. Karl-Heinz Altmann
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  1. Novartis Pharma AG, Lichtstrasse 35, 4056, Basel, Switzerland

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Altmann, KH., Memmert, K. (2008). Epothilones as lead structures for new anticancer drugs — pharmacology, fermentation, and structure-activity-relationships. In: Petersen, F., Amstutz, R. (eds) Natural Compounds as Drugs. Progress in Drug Research, vol 66. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8595-8_6

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