A common pharmacophore for epothilone and taxanes: Molecular basis for drug resistance conferred by tubulin mutations in human cancer cells
Paraskevi Giannakakou,Rick Gussio,Eva Nogales,Kenneth H. Downing,Daniel W. Zaharevitz,Birgit Bollbuck,George Poy,Dan L. Sackett,Kyriacos C. Nicolaou,Tito Fojo +9 more
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TLDR
The unification of taxane, epothilone, and sarcodictyin chemistries in a single pharmacophore provides a framework to study drug-tubulin interactions that should assist in the rational design of agents targeting tubulin.Abstract:
The epothilones are naturally occurring antimitotic drugs that share with the taxanes a similar mechanism of action without apparent structural similarity. Although photoaffinity labeling and electron crystallographic studies have identified the taxane-binding site on β-tubulin, similar data are not available for epothilones. To identify tubulin residues important for epothilone binding, we have isolated two epothilone-resistant human ovarian carcinoma sublines derived in a single-step selection with epothilone A or B. These epothilone-resistant sublines exhibit impaired epothilone- and taxane-driven tubulin polymerization caused by acquired β-tubulin mutations (β274Thr→Ile and β282Arg→Gln) located in the atomic model of αβ-tubulin near the taxane-binding site. Using molecular modeling, we investigated the conformational behavior of epothilone, which led to the identification of a common pharmacophore shared by taxanes and epothilones. Although two binding modes for the epothilones were predicted, one mode was identified as the preferred epothilone conformation as indicated by the activity of a potent pyridine-epothilone analogue. In addition, the structure–activity relationships of multiple taxanes and epothilones in the tubulin mutant cells can be fully explained by the model presented here, verifying its predictive value. Finally, these pharmacophore and activity data from mutant cells were used to model the tubulin binding of sarcodictyins, a distinct class of microtubule stabilizers, which in contrast to taxanes and the epothilones interact preferentially with the mutant tubulins. The unification of taxane, epothilone, and sarcodictyin chemistries in a single pharmacophore provides a framework to study drug–tubulin interactions that should assist in the rational design of agents targeting tubulin.read more
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References
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TL;DR: An atomic model of the αβ tubulin dimer fitted to a 3.7-Å density map obtained by electron crystallography of zinc-induced tubulin sheets is presented.
Journal Article
Epothilones, a New Class of Microtubule-stabilizing Agents with a Taxol-like Mechanism of Action
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Paclitaxel-resistant Human Ovarian Cancer Cells Have Mutant β-Tubulins That Exhibit Impaired Paclitaxel-driven Polymerization
Paraskevi Giannakakou,Dan L. Sackett,Yoon-Koo Kang,Zhirong Zhan,Jeroen Buters,Tito Fojo,Marianne S. Poruchynsky +6 more
TL;DR: Results identify residues β270 and β364 as important modulators of paclitaxel’s interaction with tubulin as well as acquired mutations in the M40 isotype at nucleotide 810 (T → G; Phe270 → Val) in 1A9PTX10 cells and nucleotide 1092 (G → A; Ala364 → Thr) in1A 9PTX22 cells.
Journal ArticleDOI
Microtubules and actin filaments: dynamic targets for cancer chemotherapy
Mary Ann Jordan,Leslie Wilson +1 more
TL;DR: By targeting microtubules, drugs inhibit cell proliferation by blocking mitosis at the mitotic checkpoint and inducing apoptosis and the antitumor potential of agents that act on the actin cytoskeleton is outlined.