A screen for kinetochore-microtubule interaction inhibitors identifies novel antitubulin compounds.

PloS One
Emanuela ScrepantiPeter De Wulf

Abstract

Protein assemblies named kinetochores bind sister chromatids to the mitotic spindle and orchestrate sister chromatid segregation. Interference with kinetochore activity triggers a spindle checkpoint mediated arrest in mitosis, which frequently ends in cell death. We set out to identify small compounds that inhibit kinetochore-microtubule binding for use in kinetochore-spindle interaction studies and to develop them into novel anticancer drugs. A fluorescence microscopy-based in vitro assay was developed to screen compound libraries for molecules that prevented the binding of a recombinant human Ndc80 kinetochore complex to taxol-stabilized microtubules. An active compound was identified that acted at the microtubule level. More specifically, by localizing to the colchicine-binding site in alphabeta-tubulin the hit compound prevented the Ndc80 complex from binding to the microtubule surface. Next, structure-activity analyses distinguished active regions in the compound and led to the identification of highly potent analogs that killed cancer cells with an efficacy equaling that of established spindle drugs. The compound identified in our screen and its subsequently identified analogs represent new antitubulin chemotypes that can...Continue Reading

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Citations

Jun 23, 2020·Biochemistry. Biokhimii︠a︡·N B UstinovN B Gudimchuk
Mar 17, 2021·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Piotr StrusIzabela Mlynarczuk-Bialy
May 26, 2011·Chemistry & Biology·Sergey TcherniukAriane Abrieu

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Methods Mentioned

BETA
gel filtration
fluorescence microscopy
GTPase
X-ray
xenograft
fluorescence imaging

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