ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism

• Published in: Nature chemical biology Vol. 3; no. 11; pp. 722 - 726
• Main Authors: Luo, Lusong, Parrish, Cynthia A, Nevins, Neysa, McNulty, Dean E, Chaudhari, Amita M, Carson, Jeffery D, Sudakin, Valery, Shaw, Antony N, Lehr, Ruth, Zhao, Huizhen, Sweitzer, Sharon, Lad, Latesh, Wood, Kenneth W, Sakowicz, Roman, Annan, Roland S, Huang, Pearl S, Jackson, Jeffrey R, Dhanak, Dashyant, Copeland, Robert A, Auger, Kurt R
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.11.2007
• Subjects: Adenosine triphosphatase; Adenosine Triphosphate - antagonists & inhibitors; Allosteric Regulation - drug effects; Animals; ATP; Binding sites; Biochemistry; Biomedical research; Cancer; Cell division; Cell Line; Cell Survival - drug effects; Cellular biology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Inhibitor drugs; Inhibitors; Inhibitory Concentration 50; Models, Molecular; Molecular Structure; Mutation; Protein Kinases - chemistry; Protein Kinases - metabolism; Protein Structure, Tertiary; Proteins; Side effects
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.2007.34

The mitotic kinesin KSP (kinesin spindle protein, or Eg5) has an essential role in centrosome separation and formation of the bipolar mitotic spindle. Its exclusive involvement in the mitotic spindle of proliferating cells presents an opportunity for developing new anticancer agents with reduced side effects relative to antimitotics that target tubulin. Ispinesib (1) is an allosteric small-molecule KSP inhibitor in phase 2 clinical trials. Mutations that attenuate ispinesib binding to KSP have been identified, which highlights the need for inhibitors that target different binding sites. We describe a new class of selective KSP inhibitors that are active against ispinesib-resistant forms of KSP. These ATP-competitive KSP inhibitors do not bind in the nucleotide binding pocket. Cumulative data from generation of resistant cells, site-directed mutagenesis and photo-affinity labeling suggest that they compete with ATP binding via a novel allosteric mechanism.