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Preclinical Pharmacology and Structure-Activity Studies of Epothilones

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The Epothilones: An Outstanding Family of Anti-Tumor Agents

Abstract

Microtubule inhibitors are an important class of anticancer agents (1), with clinical applications in the treatment of a variety of cancer types, either as single agents or as part of different combination regimens (2, 3). Microtubule-interacting agents can be grouped into two distinct functional classes, namely, compounds that inhibit the assembly of tubulin heterodimers into microtubule polymers (“tubulin polymerization inhibitors”) and those that stabilize microtubules under normally destabilizing conditions (“microtubule stabilizers”) (4). The latter will also promote the assembly of tubulin heterodimers into microtubule polymers and, as will be discussed later, the induction of tubulin polymerization is often used as a biochemical readout for a quantitative assessment of the interaction of microtubule-stabilizing agents with tubulin. Tubulin polymerization inhibitors such as vincristine and vinblastine have been employed in cancer therapy for more than 40 years (vincristine and vinblastine received FDA approval in 1963 and 1965, respectively). In contrast, the clinical history of microtubule-stabilizing agents is significantly shorter and its beginning dates back no more than 15 years. The first microtubule stabilizer to be introduced into clinical practice was the natural product taxol (paclitaxel; Taxol®) in 1993 (Fig. 1), with FDA approval for the semi-synthetic taxol analog docetaxel (Taxotere®) following three years later. Both compounds rapidly became an important part of today’s armamentarium in the battle against cancer,which marks the emergence of microtubule-stabilizing anti-cancer drugs as an important milestone in the development of modern cancer chemotherapy (5).

Molecular structures of taxol and its semi-synthetic analog docetaxel

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  1. Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Hönggerberg. HCI H 405, ETH Zürich, Wolfgang-Pauli-Str. 10, 8093, Zürich, Switzerland

    Prof. Dr. Karl-Heinz Altmann

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Altmann, KH. (2009). Preclinical Pharmacology and Structure-Activity Studies of Epothilones. In: The Epothilones: An Outstanding Family of Anti-Tumor Agents. Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products, vol 90. Springer, Vienna. https://doi.org/10.1007/978-3-211-78207-1_5

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