BTB-1 : a small molecule inhibitor of the mitotic motor protein Kif18A

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Catarinella_Angew_Chem_2009.pdf
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The survival and development of each organism relies on the equal partitioning of its genome during cell division. Errors in this process can lead to severe developmental defects and cancer in humans. Key for the accurate distribution of the genome is the mitotic spindle composed of dynamic microtubules (Mts).[1] The shape and function of the mitotic spindle depends on the concerted action of various kinesins, these are molecular motor proteins which as microtubule-stimulated ATPases convert chemical energy into mechanical force. Recently, we identified the kinesin-8 member Kif18A as a central component for the correct alignment of chromosomes at the spindle equator.[2] Furthermore, in vitro analyses revealed that Kif18A distinguishes itself from all other kinesins by its dual functionality: motility and depolymerase activity.[2 4] Owing to their fast and often reversible mode of action, small molecules are ideally suited to dissect the function and mechanism of proteins. Given the complex enzymatic characteristics of Kif18A, we set up a smallmolecule screen to identify inhibitors of Kif18A. Herein we report the discovery of BTB-1 (Figure 1a), the first smallmolecule inhibitor of Kif18A. We show that BTB-1 potently inhibits the ATPase activity of Kif18A (IC50=1.69 mm) but not of other tested key mitotic kinesins. BTB-1 blocks the motility of Kif18A in a reversible manner. Notably, BTB-1 inhibits Kif18A in an adenosine triphosphate(ATP)-competitive but microtubule-uncompetitive manner and slows down the progression of cells through mitosis.

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540 Chemie
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antiproliferation, enzymes, inhibitors, mitosis, molecular motors
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ISO 690CATARINELLA, Mario, Tamara GRÜNER, Tobias STRITTMATTER, Andreas MARX, Thomas U. MAYER, 2009. BTB-1 : a small molecule inhibitor of the mitotic motor protein Kif18A. In: Angewandte Chemie : International Edition. 2009, 48(48), pp. 9072-9076. ISSN 1433-7851. eISSN 1521-3773. Available under: doi: 10.1002/anie.200904510
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@article{Catarinella2009small-10061,
  year={2009},
  doi={10.1002/anie.200904510},
  title={BTB-1 : a small molecule inhibitor of the mitotic motor protein Kif18A},
  number={48},
  volume={48},
  issn={1433-7851},
  journal={Angewandte Chemie : International Edition},
  pages={9072--9076},
  author={Catarinella, Mario and Grüner, Tamara and Strittmatter, Tobias and Marx, Andreas and Mayer, Thomas U.}
}
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    <dcterms:abstract xml:lang="eng">The survival and development of each organism relies on the equal partitioning of its genome during cell division. Errors in this process can lead to severe developmental defects and cancer in humans. Key for the accurate distribution of the genome is the mitotic spindle composed of dynamic microtubules (Mts).[1] The shape and function of the mitotic spindle depends on the concerted action of various kinesins, these are molecular motor proteins which as microtubule-stimulated ATPases convert chemical energy into mechanical force. Recently, we identified the kinesin-8 member Kif18A as a central component for the correct alignment of chromosomes at the spindle equator.[2] Furthermore, in vitro analyses revealed that Kif18A distinguishes itself from all other kinesins by its dual functionality: motility and depolymerase activity.[2 4] Owing to their fast and often reversible mode of action, small molecules are ideally suited to dissect the function and mechanism of proteins. Given the complex enzymatic characteristics of Kif18A, we set up a smallmolecule screen to identify inhibitors of Kif18A. Herein we report the discovery of BTB-1 (Figure 1a), the first smallmolecule inhibitor of Kif18A. We show that BTB-1 potently inhibits the ATPase activity of Kif18A (IC50=1.69 mm) but not of other tested key mitotic kinesins. BTB-1 blocks the motility of Kif18A in a reversible manner. Notably, BTB-1 inhibits Kif18A in an adenosine triphosphate(ATP)-competitive but microtubule-uncompetitive manner and slows down the progression of cells through mitosis.</dcterms:abstract>
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