Mechanism of Inhibition of Human KSP by Ispinesib

KSP, also known as HsEg5, is a kinesin that plays an essential role in the formation of a bipolar mitotic spindle and is required for cell cycle progression through mitosis. Ispinesib is the first potent, highly specific small-molecule inhibitor of KSP tested for the treatment of human disease. This...

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Bibliographic Details
Published in:Biochemistry (Easton) 2008-03, Vol.47 (11), p.3576-3585
Main Authors: Lad, Latesh, Luo, Lusong, Carson, Jeffrey D., Wood, Kenneth W., Hartman, James J., Copeland, Robert A., Sakowicz, Roman
Format: Article
Language:English
Subjects:
Adenosine Diphosphate - antagonists & inhibitors
Adenosine Diphosphate - secretion
Adenosine Triphosphatases - antagonists & inhibitors
Adenosine Triphosphate - physiology
Allosteric Regulation - genetics
Benzamides - chemistry
Benzamides - metabolism
Binding, Competitive - genetics
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Humans
Kinesin - antagonists & inhibitors
Kinesin - chemistry
Kinesin - genetics
Kinesin - metabolism
Microtubules - genetics
Microtubules - metabolism
Models, Biological
Models, Chemical
Protein Binding - genetics
Protein Structure, Tertiary - genetics
Quinazolines - chemistry
Quinazolines - metabolism
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Summary:KSP, also known as HsEg5, is a kinesin that plays an essential role in the formation of a bipolar mitotic spindle and is required for cell cycle progression through mitosis. Ispinesib is the first potent, highly specific small-molecule inhibitor of KSP tested for the treatment of human disease. This novel anticancer agent causes mitotic arrest and growth inhibition in several human tumor cell lines and is currently being tested in multiple phase II clinical trials. In this study we have used steady-state and pre-steady-state kinetic assays to define the mechanism of KSP inhibition by ispinesib. Our data show that ispinesib alters the ability of KSP to bind to microtubules and inhibits its movement by preventing the release of ADP without preventing the release of the KSP−ADP complex from the microtubule. This type of inhibition is consistent with the physiological effect of ispinesib on cells, which is to prevent KSP-driven mitotic spindle pole separation. A comparison of ispinesib to monastrol, another small-molecule inhibitor of KSP, reveals that both inhibitors share a common mode of inhibition.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi702061g