Mechanism of inhibition of human KSP by Ispinesib

Biochemistry

Volumn 47, Issue 11, 2008, Pages 3576-3585

  Lad, Latesh ^b   Luo, Lusong ^a   Carson, Jeffrey D ^a   Wood, Kenneth W ^b   Hartman, James J ^b   Copeland, Robert A ^a   Sakowicz, Roman ^b  

^a GLAXOSMITHKLINE   (United States)

^b Cytokinetics Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICANCER AGENT;

BIOASSAY; CELL GROWTH; DISEASES; PHYSIOLOGY;

ENZYME INHIBITION;

ADENOSINE DIPHOSPHATE; ANTINEOPLASTIC AGENT; ENZYME INHIBITOR; ISPINESIB; KINESIN; MONASTROL; PROTEIN KSP; UNCLASSIFIED DRUG;

ARTICLE; CANCER CELL CULTURE; CELL CYCLE PROGRESSION; DRUG BINDING; DRUG HALF LIFE; DRUG MECHANISM; DRUG POTENCY; HUMAN CELL CULTURE; MICROTUBULE; MITOSIS INHIBITION; MITOSIS SPINDLE; PRIORITY JOURNAL; STEADY STATE;

ADENOSINE DIPHOSPHATE; ADENOSINE TRIPHOSPHATASES; ADENOSINE TRIPHOSPHATE; ALLOSTERIC REGULATION; BENZAMIDES; BINDING, COMPETITIVE; ENZYME INHIBITORS; HUMANS; KINESIN; MICROTUBULES; MODELS, BIOLOGICAL; MODELS, CHEMICAL; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; QUINAZOLINES;

EID: 40849137762     PISSN: 00062960     EISSN: None     Source Type: Journal    
DOI: 10.1021/bi702061g     Document Type: Article

References (31)

1. Wood, K., Cornwell, W., and Jackson, J. (2001) Past and future of the mitotic spindle as an onclogy target. Curr. Opin. Pharmacol. 1, 370-377.
2. Sakowicz, R., Finer, J. T., Beraud, C., Crompton, A., Lewis, E., Fritsch, A., Lee, Y., Mak, J., Moody, R., Turincio, R., Chabala, J. C., Gonzales, P., Roth, S., Weitman, S., and Wood, K. W. (2004) Antitumor activity of a kinesin inhibitor. Cancer Res. 64, 3276-3280.
3. Kapitein, L. C., Peterman, E. J., Kwok, B. H., Kim, J. H., Kapoor, T. M., and Schmidt, C. F. (2005) The bipolar mitotic kinesin Eg5 moves on both microtubules that it crosslinks. Nature 435, 114-118.
4. Blangy, A., Arnaud, L., and Nigg, E. A. (1997) Phosphorylation by p34cdc2 protein kinase regulates binding of the kinesin-related motor HsEg5 to the dynactin subunit p150. J. Biol. Chem. 272, 19418-19424.
5. Cole, D. G., Saxton, W. M., Sheehan, K. B., and Scholey, J. M. (1994) A "slow" homotetrameric kinesin-related motor protein purified from Drosophila embryos. J. Biol. Chem. 269, 22913-22916.
6. Kashina, A. S., Baskin, R. J., Cole, D. G., Wedaman, K. P., Saxton, W. M., and Scholey, J. M. (1996) A bipolar kinesin. Nature 379, 270-272.
7. Marcus, A. I., Peters, U., Thomas, S. L., Garrett, S., Zelnak, A., Kapoor, T. M., and Giannakakou, P. (2005) Mitotic kinesin inhibitors induce mitotic arrest and cell death in Taxol-resistant and -sensitive cancer cells. J. Biol. Chem. 280, 11569-11577.
8. Sharp, D. J., McDonald, K. L., Brown, H. M., Matthies, H. J., Walczak, C., Vale, R. D., Mitchison, T. J., and Scholey, J. M. (1999) The bipolar kinesin, KLP61F, cross-links microtubules within interpolar microtubule bundles of Drosophila embryonic mitotic spindles. J. Cell Biol. 144, 125-138.
9. DeBonis, S., Simorre, J. P., Crevel, I., Lebeau, L., Skoufias, D. A., Blangy, A., Ebel, C., Gans, P., Cross, R., Hackney, D. D., Wade, R. H., and Kozielski, F. (2003) Interaction of the mitotic inhibitor monastrol with human kinesin Eg5. Biochemistry 42, 338-349.
10. Kapoor, T. K., Mayer, T. U., Coughlin, M. L., and Mitchinson, T. J. (2000) Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J. Cell Biol. 150, 975-988.
11. Maliga, Z., Kapoor, T. K., and Mitchinson, T. J. (2002) Evidence that monastrol is an allosteric inhibitor of the mitotic kinesin Eg5. Chem. Biol. 9, 989-996.
12. Mayer, T. U., Kapoor, T. K., Haggarthy, S. J., King, R. W., Schreiber, S. L., and Mitchinson, T. J. (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286, 971-974.
13. Yan, Y., Sardana, V., Xu, B., Homnick, C., Halczenko, W., Buser, C. A., Schaber, M., Hartman, G. D., Huber, H. E., and Kou, L. C. (2004) Inhibition of a mitotic motor protein: where, how, and conformational consequences. J. Mol. Biol. 335, 547-543.
14. Blangy, A., Lane, H. A., d'Herin, P., Harper, M., Kress, M., and Nigg, E. A. (1995) Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83, 1159-1169.
15. Sawin, K. E., LeGuellec, K., Philippe, M., and Mitchinson, T. J. (1992) Mitotic spindle organization by a plus-end-directed microtubule motor. Nature 359, 540-543.
16. Luo, L., Carson, J. D., Dhanak, D., Jackson, J. R., Huang, P. S., Lee, Y., Sakowicz, R., and Copeland, R. A. (2004) Mechanism of inhibition of human KSP by monastrol: insights from kinetic analysis and the effect of ionic strength on KSP inhibition. Biochemistry 43, 15258-15266.
17. Cochran, J. C., Gatial, J. E., Kapoor, T. M., and Gilbert, S. P. (2005) Monastrol inhibition of the mitotic kinesin Eg5. J. Biol. Chem. 280, 12658-12667.
18. Cochran, J., and Gilbert, S. P. (2005) ATPase mechanism of Eg5 in the absence of microtubules: insight into microtubule activation and allosteric inhibition by monastrol. Biochemistry 44, 16633-16648.
19. Johnson, R. K., McCabe, F. L., Cauder, E., Innlow, L., Whitacare, M., Winkler, J. D., Bergnes, G., Feng, B., Smith, W. W., Morgans, D., and Wood, K. (2002) SB-715992. a potent and selective inhibitor of KSP mitotic kinesin, demonstrates broad-spectrum activity in advanced murine tumors and human tumor xenografts. Proc. Am. Assoc. Cancer Res. 43, 1335.
20. Morrison, J. F. (1969) Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors. Biochim. Biophys. Acta 185, 269-286.
21. Gilbert, S. P., and Mackey, A. T. (2000) Kinetics: a tool to study molecular motors. Methods 22, 337-354.
22. Brune, M., Hunter, J. L., Corrie, J. E., and Webb, M. R. (1994) Direct, real-time measurement of rapid inorganic phosphate release using a novel fluorescent probe and its application to actomyosin subfragment 1 ATPase. Biochemistry 33, 8262-8271.
23. Cochran, J., Sontag, C. A., Maliga, Z., Kapoor, T. M., Correia, J. J., and Gilbert, S. P. (2004) Mechanistic analysis of the mitotic kinesin Eg5. J. Biol. Chem. 279, 38861-38870.
24. Vale, R. D., and Milligan, R. A. (2000) The way things move: looking under the hood of molecular motor proteins. Science 288, 88-95.
25. Yang, J. T., Saxton, W. M., Stewart, R. J., Raff, E. C., and Goldstein, L. S. (1990) Evidence that the head of kinesin is sufficient for force generation and motility in vitro. Science 249, 42-47.
26. Bergnes, G., Ha, E., Yiannikourous, G., Kalantis, P., Yonce, B. E., and Welday, K. A. (2003) Synthesis of quinazolinones, U.S. Patent WO-03070701.
27. Finer, J. T., Bergnes, G., Feng, B., Smith, W. W., Chabala, J. C., and Morgans, D. J. (2001) Methods and compositions utilizing quinazolinones, U.S. Patent WO-00198278.
28. Cochran, J., Krzysiak, T. C., and Gilbert, S. P. (2006) Pathway of ATP hydrolysis by monomelic kinesin Eg5. Biochemistry 45, 12334-12344.
29. Jackson, J. R., Auger, K. R., Gilmartin, A., Eng, W. K., Luo, L., Concha, N., Parrish, C., Sutton, D., Diamond, M., Giardiniere, M., Zhang, S., Huang, P., Belmont, L., Lee, Y., Bergnes, G., Anderson, R., Wood, K. W., and Sakowicz, R. (2005) A Resistance Mechanism for the KSP Inhibitor Ispinesib Implicates Point Mutations in the Compound Binding Site,AACR-NCI-EORTC C207.
30. Maliga, Z., Xing, J., Cheung, H., Juszczak, L. J., Friedman, J. M., and Rosenfeld, S. S. (2006) A pathway of structural changes produced by monastrol binding to Eg5. J. Biol. Chem. 281, 7977-7982.
31. Kikkawa, M., Sablin, E. P., Okada, Y., Yajima, H., Fletterick, R. J., and Hirokawa, N. (2001) Switch-based mechanism of kinesin motors. Nature 411, 439-445.