Microtubule-Targeting Agents: Strategies To Hijack the Cytoskeleton

doi:10.1016/j.tcb.2018.05.001

Trends in Cell Biology

Volume 28, Issue 10, October 2018, Pages 776-792

https://doi.org/10.1016/j.tcb.2018.05.001 Get rights and content

Highlights

Structural biology has allowed the identification and detailed characterization of six distinct ligand-binding sites on tubulin. Two sites are targeted by microtubule-stabilizing agents (MSAs); four sites are targeted by microtubule-destabilizing agents (MDAs).

MSAs stabilize microtubules by strengthening lateral and/or longitudinal tubulin contacts in microtubules. MDAs destabilize microtubules by either inhibiting the formation of native tubulin contacts or by hindering the curved-to-straight conformational change of tubulin accompanying microtubule formation.

Different types of anticancer agents that were initially developed against kinases were found to bind also to tubulin as an off-target.

Microtubule-targeting agents (MTAs) such as paclitaxel and the vinca alkaloids are among the most important medical weapons available to combat cancer. MTAs interfere with intracellular transport, inhibit eukaryotic cell proliferation, and promote cell death by suppressing microtubule dynamics. Recent advances in the structural analysis of MTAs have enabled the extensive characterization of their interactions with microtubules and their building block tubulin. We review here our current knowledge on the molecular mechanisms used by MTAs to hijack the microtubule cytoskeleton, and discuss dual inhibitors that target both kinases and microtubules. We further formulate some outstanding questions related to MTA structural biology and present possible routes for future investigations of this fascinating class of antimitotic agents.

Section snippets

Agents Targeting the Microtubule Cytoskeleton

The microtubule cytoskeleton (see Glossary) plays pivotal roles in several biological functions, ranging from intracellular trafficking and positioning of cellular components in interphase, the formation of the mitotic spindle during cell division, to the establishment and maintenance of cell morphology and cell motility (reviewed in 1, 2, 3). Because of being implicated in such key cellular activities, compounds that interfere with microtubule cytoskeleton functions have been developed as

Taxane-Site Ligands

The first atomic level description of the binding of an MTA to tubulin was paclitaxel, whose structure was solved in 1998 based on electron crystallography data obtained from tubulin–paclitaxel zinc-sheets 9, 10. Almost two decades later, X-ray crystallography and cryo-EM enabled the structural elucidation of taxane-site MSAs bound to tubulin to high resolution, including epothilone, zampanolide, discodermolide, and taccalonolide (Table 1). All these agents bind to a pocket of β-tubulin located

Colchicine-Site Ligands

Colchicine-site ligands are probably the most extensively studied class of MTAs; however, none of them have reached the commercial phase yet. Since the first atomic description of colchicine binding to tubulin in 2004 [23], a large number of structurally diverse colchicine-site ligands of natural or synthetic origin in complex with tubulin have been characterized by X-ray crystallography to medium and high resolution (Table 1).

The colchicine site is a deep pocket mostly buried in the

Kinase Inhibitors that Target Microtubules

As mentioned earlier, MTAs are very diverse both in terms of chemical structures and molecular weights. Furthermore, some binding pockets on tubulin, such as the colchicine and the taxane sites, are fairly deep, large in size, and predominantly hydrophobic in nature. It is thus not surprising that several different types of anticancer drugs that were initially developed against other protein targets such as, for example, kinases turned out to also bind tubulin and to display off-target effects

Concluding Remarks and Future Perspectives

Recent breakthroughs in the tubulin structural biology field have enabled the discovery and detailed characterization of new ligand-binding sites on tubulin and deciphering the molecular mechanisms of action of a large number MTAs. While both X-ray crystallography and cryo-EM provide detailed, albeit static, views of tubulin/microtubule–MTA interactions, acquiring information on how ligands affect the functionally crucial dynamics of the αβ-tubulin heterodimer as well as of the shaft and ends

Acknowledgments

M.O.S. is supported by a grant from the Swiss National Science Foundation (31003A_166608).

Glossary

Apoptosis: a biochemical process leading to cell death.
Allostery: the process by which proteins transmit the effect of binding at one site to another, often distal, site.
Antibody–drug conjugates (ADCs): complex molecules composed of an antibody linked to a cytotoxic agent, which are used in targeted anticancer therapy.
Cryo-electron microscopy (cryo-EM): transmission EM carried out at cryogenic temperatures. The method allows the structural analysis of vitrified macromolecules at high resolution.

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Trends in Cell Biology

ReviewMicrotubule-Targeting Agents: Strategies To Hijack the Cytoskeleton

Highlights

Section snippets

Agents Targeting the Microtubule Cytoskeleton

Taxane-Site Ligands

Colchicine-Site Ligands

Kinase Inhibitors that Target Microtubules

Concluding Remarks and Future Perspectives

Acknowledgments

Glossary

Cancer Treat. Rev.

J. Mol. Biol.

Cell

J. Mol. Biol.

J. Biol. Chem.

Curr. Biol.

Cancer Lett.

Curr. Biol.

Mol. Pharmacol.

Biochem. Biophys. Res. Commun.

Cancer Lett.

Chem. Biol.

J. Mol. Biol.

J. Mol. Biol.

Prog. Biophys. Mol. Biol.

FEBS Lett.

Dev. Cell

Cell

Trends Biochem. Sci.

Semin. Cell Dev. Biol.

Biochem. Biophys. Res. Commun.

Bioorg. Med. Chem.

J. Mol. Biol.

Chem

Eur. J. Med. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Structural plasticity in actin and tubulin polymer dynamics

Science

The centrosome in cells and organisms

Science

Control of microtubule organization and dynamics: two ends in the limelight

Nat. Rev. Mol. Cell Biol.

Microtubule-binding agents: a dynamic field of cancer therapeutics

Nat. Rev. Drug Discov.

Taxol®: the first microtubule stabilizing agent

Int. J. Mol. Sci.

Microtubules and resistance to tubulin-binding agents

Nat. Rev. Cancer

Beyond taxol: microtubule-based treatment of disease and injury of the nervous system

Brain

Structure of the alpha beta tubulin dimer by electron crystallography

Nature

Mechanism of microtubule stabilization by taccalonolide AJ

Nat. Commun.

Molecular mechanism of action of microtubule-stabilizing anticancer agents

Science

Structural basis of microtubule stabilization by discodermolide

ChemBioChem

Zampanolide binding to tubulin indicates cross-talk of taxane site with colchicine and nucleotide sites

J. Nat. Prod.

Peloruside A, a novel antimitotic agent with paclitaxel-like microtubule-stabilizing activity

Cancer Res.

Laulimalide and isolaulimalide, new paclitaxel-like microtubule-stabilizing agents

Cancer Res.

Structural basis of microtubule stabilization by laulimalide and peloruside A

Angew. Chem. Int. Ed. Engl.

Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain

Nature

Variations in the colchicine-binding domain provide insight into the structural switch of tubulin

Proc. Natl. Acad. Sci. U. S. A.

The tubulin colchicine domain: a molecular modeling perspective

ChemMedChem

Blocking blood flow to solid tumors by destabilizing tubulin: an approach to targeting tumor growth

J. Med. Chem.

The vinca alkaloids: a new class of oncolytic agents

Cancer Res.

The dolastatins

Review
Microtubule-Targeting Agents: Strategies To Hijack the Cytoskeleton

Taxol^®: the first microtubule stabilizing agent