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Taccalonolide Microtubule Stabilizers

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Progress in the Chemistry of Organic Natural Products 112

Part of the book series: Progress in the Chemistry of Organic Natural Products ((POGRCHEM,volume 112))

Abstract

Microtubule stabilizers are a mainstay in the treatment of many solid cancers and continue to find utility in combination therapy with molecularly targeted anticancer agents and immunotherapeutics. However, innate and acquired resistance to microtubule stabilizers can limit their clinical efficacy. The taccalonolides are a unique class of microtubule stabilizers isolated from plants of Tacca that circumvent clinically relevant mechanisms of drug resistance. Although initial reports suggested that the microtubule-stabilizing activity of the taccalonolides was independent of direct tubulin binding, additional studies have identified that potent C-22, C-23 epoxidized taccalonolides covalently bind the Aspartate 226 residue of β-tubulin and that this interaction is critical for their microtubule-stabilizing activity. The taccalonolides have distinct properties as compared to other microtubule stabilizers with regard to their biochemical effects on tubulin structure and dynamics that promote distinct cellular phenotypes. Some taccalonolides have demonstrated in vivo antitumor efficacy in drug-resistant tumor models with exquisite potency and long-lasting antitumor efficacy as a result of their irreversible target engagement. The recent identification of a site on the taccalonolide scaffold that is amenable to modification has provided evidence of the specificity of the taccalonolide–tubulin interaction. This also affords an opportunity to further optimize the targeted delivery of the taccalonolides to further improve their anticancer efficacy and potential for clinical development.

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Author information

Authors and Affiliations

  1. Department of Pharmacology, The University of Texas Health Science Center at San Antonio, Floyd Curl Drive, 78229, San Antonio, TX, USA

    Samantha S. Yee & April L. Risinger

  2. Department of Chemistry and Biochemistry and Institute for Natural Products Applications and Research Technologies, The University of Oklahoma, 101 Stephenson Parkway, 73019, Norman, OK, USA

    Lin Du

Authors
  1. Samantha S. Yee
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  2. Lin Du
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  3. April L. Risinger
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Corresponding authors

Correspondence to Samantha S. Yee or April L. Risinger .

Editor information

Editors and Affiliations

  1. College of Pharmacy, The Ohio State University, Columbus, OH, USA

    A. Douglas Kinghorn

  2. Institute of Organic Chemistry, Johannes Kepler University, Linz, Oberösterreich, Austria

    Heinz Falk

  3. School of Pharmacy, University of East Anglia, Norwich, UK

    Simon Gibbons

  4. Graduate School of Pharmaceutical Science, Hokkaido University, Fukuoka, Japan

    Jun'ichi Kobayashi

  5. Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan

    Yoshinori Asakawa

  6. School of Pharmaceutical Sciences, South Central University for Nationalities, Wuhan, China

    Ji-Kai Liu

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Yee, S.S., Du, L., Risinger, A.L. (2020). Taccalonolide Microtubule Stabilizers. In: Kinghorn, A.D., Falk, H., Gibbons, S., Kobayashi, J., Asakawa, Y., Liu, JK. (eds) Progress in the Chemistry of Organic Natural Products 112. Progress in the Chemistry of Organic Natural Products, vol 112. Springer, Cham. https://doi.org/10.1007/978-3-030-52966-6_3

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