Novel benzimidazole inhibitors bind to a unique site in the kinesin spindle protein motor domain

Biochemistry

Volumn 49, Issue 38, 2010, Pages 8350-8358

  Sheth, Payal R ^a   Shipps, Gerald W ^a   Seghezzi, Wolfgang ^a   Smith, Catherine K ^a   Chuang, Cheng Chi ^a   Sanden, David ^a   Basso, Andrea D ^a   Vilenchik, Lev ^a   Gray, Kimberly ^a   Annis, D Allen ^b   Nickbarg, Elliott ^a   Ma, Yao ^a   Lahue, Brian ^a   Herbst, Ronald ^c   Le, Hung V ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b Aileron Therapeutics Inc   (United States)

^c MEDIMMUNE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DICHROISM; DRUG THERAPY; GROWTH KINETICS; MASS SPECTROMETRY;

AFFINITY SELECTION; ATP-ASE ACTIVITY; BENZIMIDAZOLES; BINDING POCKETS; BINDING STUDIES; BIPOLAR SPINDLES; BREAST CANCER; CANCER CELL GROWTH; CIRCULAR DICHROISM; CLINICAL TRIAL; COMBINATION THERAPY; DATA SUPPORT; DOUBLE MUTANTS; IN-PHASE; INHIBITORY SITES; KINESINS; PROTEIN MOTORS; RESISTANT MUTANTS; SINGLE-AGENT; SMALL MOLECULES; TEMPERATURE DEPENDENT;

ENZYME INHIBITION;

ADENOSINE TRIPHOSPHATASE; BENZIMIDAZOLE DERIVATIVE; ISPINESIB; KINESIN; KINESIN SPINDLE PROTEIN; NUCLEOTIDE; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; BENZAMIDE DERIVATIVE; BENZIMIDAZOLE; KIF11 PROTEIN, HUMAN; QUINAZOLINE DERIVATIVE;

AFFINITY SELECTION MASS SPECTROMETRY; ARTICLE; BINDING SITE; CANCER GROWTH; CANCER INHIBITION; CANCER RESISTANCE; CIRCULAR DICHROISM; COMPETITIVE INHIBITION; CONTROLLED STUDY; DRUG BINDING; DRUG TARGETING; ENZYME ACTIVITY; ENZYME INHIBITION; FEMALE; HUMAN; HUMAN CELL; MASS SPECTROMETRY; MITOSIS INHIBITION; MITOSIS SPINDLE; MUTANT; NONHUMAN; PREDICTION; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DOMAIN; TEMPERATURE DEPENDENCE; ANTAGONISTS AND INHIBITORS; CHEMISTRY; METABOLISM; PROTEIN TERTIARY STRUCTURE;

ADENOSINE TRIPHOSPHATASES; ANTINEOPLASTIC AGENTS; BENZAMIDES; BENZIMIDAZOLES; BINDING SITES; CIRCULAR DICHROISM; HUMANS; KINESIN; MASS SPECTROMETRY; NUCLEOTIDES; PROTEIN STRUCTURE, TERTIARY; QUINAZOLINES;

EID: 77957081365     PISSN: 00062960     EISSN: 15204995     Source Type: Journal    
DOI: 10.1021/bi1005283     Document Type: Article

References (31)

1. Miki, H., Okada, Y., and Hirokawa, N. (2005) Analysis of the kinesin superfamily: Insights into structure and function Trends Cell Biol. 15, 467-476
2. Sharp, D. J., Rogers, G. C., and Scholey, J. M. (2000) Microtubule motors in mitosis Nature 407, 41-47
3. Valentine, M. T. and Gilbert, S. (2007) To step or not to step? How biochemistry and mechanics influence processivity in kinesin and Eg5 Curr. Opin. Cell Biol. 19, 75-81
4. Bergnes, G., Brejc, K., and Belmont, L. (2005) Mitotic kinesins: Prospects for antimitotic drug discovery Curr. Top. Med. Chem. 5, 127-145
5. Yan, Y., Sardana, V., Xu, B., Homnick, C., Halczenko, W., Buser, C. A., Schaber, M., Hartman, G. D., Huber, H. E., and Kuo, L. C. (2004) Inhibition of a mitotic motor protein: Where, how and conformational consequences J. Mol. Biol. 335, 547-554
6. Heald, R. (2000) Motor function in the mitotic spindle minireview Cell 102, 399-402
7. 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
8. Mayer, T. U., Kapoor, T. M., Haggarty, S. J., King, R. W., Schreiber, S. L., and Mitchison, T. J. (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen Science 286, 971-974
9. Cox, C. D., Torrent, M., Breslin, M. J., Mariano, B. J., Whitman, D. B., Coleman, P. J., Buser, C. A., Walsh, E. S., Hamilton, K., Schaber, M., Lobell, R. B., Tao, W., South, V. J., Kohl, N. E., Yan, Y., Kuo, L. C., Prueksaritanont, T., Slaughter, D. E., Li, C., Mahan, E., Lu, B., and Hartman, G. D. (2006) Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent and water soluble inhibitors of the mitotic kinesin KSP Bioorg. Med. Chem. Lett. 16, 3175-3179
10. Kim, K. S., Lu, S., Cornelius, L. A., Lombardo, L. J., Borzilleri, R. M., Schroeder, G. M., Sheng, C., Rovnyak, G., Crews, D., Schmidt, R. J., Williams, D. K., Bhide, R. S., Traeger, S. C., McConnell, P. A., Mueller, L., Sheriff, S., Newitt, J. A., Pudzianowski, A., Yang, Z., Wild, R., Lee, F. Y., Batorsky, R., Ryder, J. S., Ortega-Nanos, M., Shen, H., Gottardis, M., and Roussell, D. L. (2006) Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors Bioorg. Med. Chem. Lett. 16, 3937-3942
11. Cox, C. D., Coleman, P. J., Breslin, M. J., Whitman, D. B., Garbaccio, R. M., Fraley, M. E., Buser, C. A., Walsh, E. S., Schaber, M. D., Lobell, R. B., Tao, W., Davide, J. P., Diehl, R. E., Abrams, M. T., South, V. J., Huber, H. E., Torrent, M., Prueksaritanont, T., Li, C., Slaughter, D. E., Mahan, E., Fernandez-Metzler, C., Yan, Y., Kuo, L. C., Kohl, N. E., and Hartman, G. D. (2008) Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl] -2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer J. Med. Chem. 51, 4239-4252
12. DeBonis, S., Skoufias, D. A., Indorato, R.-L., Liger, F., Marquet, B., Laggner, C., Benoit, J., and Kozielski, F. (2008) Structure-activity relationship of S-trityl- l -cysteine analogues as inhibitors of the human mitotic kinesin Eg5 J. Med. Chem. 51, 1115-1125
13. Parrish, C. A., Adams, N. A., Auger, K. R., Burgess, J. L., Carson, J. D., Chaudhari, A. M., Copeland, R. A., Diamond, M. A., Donatelli, C. A., Duffy, K. J., Faucetta, L. F., Finer, J. T., Huffman, W. F., Hugger, E. D., Jackson, J. R., Knight, S. D., Luo, L., Moore, M. L., Newlander, K. A., Ridgers, L. H., Sakowicz, R., Shaw, A. N., Sung, C.-m. M., Sutton, D., Wood, K. W., Zhang, S.-Y., Zimmerman, M. N., and Dhanak, D. (2007) Novel ATP-competitive kinesin spindle protein inhibitors J. Med. Chem. 50, 4939-4952
14. Luo, L., Parrish, C. A., Neysa, N., McNulty, D. E., Chaudhari, A. M., Carson, J. D., Sudakin, V., Shaw, A. N., Lehr, R., Zhao, H., Sweitzer, S., Lad, L., Wood, K. W., Sakowicz, R., Annan, R. S., Huang, P. S., Jackson, J. R., Dhanak, D., Copeland, R. A., and Auger, K. R. (2007) ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism Nat. Chem. Biol. 3, 722-726
15. Zhang, B., Liu, J.-F., Xu, Y., and Ng, S.-C. (2008) Crystal structure of HsEg5 in complex with clinical candidate CK0238273 provides insight into inhibitory mechanism, potency and specificity Biochem. Biophys. Res. Commun. 372, 565-570
16. Annis, D. A., Athanasopoulos, J., Curran, P. J., Felsch, J. S., Kalghatgi, K., Lee, W. H., Nash, H. M., Orminati, J.-P. A., Rosner, K. E., Shipps, G. W., Jr., Thaddupathy, G. R. A., Tyler, A. N., Vilenchik, L., Wagner, C. R., and Wintner, E. A. (2004) An affinity selection-mass spectrometry method for the identification of small molecule ligands for self-encoded combinatorial libraries: Discovery of a novel antagonist of E. coli dihydrofolate reductase Int. J. Mass Spectrom. 238, 77-83
17. Annis, D. A., Nickbarg, E., Yang, X., Ziebell, M. R., and Whitehurst, C. E. (2007) Affinity selection-mass spectrometry screening techniques for small molecule discovery Curr. Opin. Chem. Biol. 11, 518-526
18. Jackson, J. R., Auger, K. R., Gilmartin, A., Wai, E. K., Luo, L., Concha, N., Parrish, C. A., Sutton, D., Diamond, M. A., Giardiniere, M., Zhang, S.-Y., Huang, P. S., Wood, K. W., Belmont, L., Lee, Y., Bergnes, G., Anderson, R., Brejc, K., and Sakowicz, R. (2005) A resistance mechanism for the KSP inhibitor ispinesib implicates point mutations in the compound binding site, in Proceedings of the AAC-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting (AACR, Philadephia, 2005), Philadelphia, PA.
19. Lahue, B. R., Ma, Y., Shipps, G. W., Jr., Seghezzi, W., and Herbst, R. (2009) Substituted benzimidazoles: A novel chemotype for small molecule hKSP inhibitors Bioorg. Med. Chem. Lett. 19, 3405-3409
20. Sheth, P. R., Basso, A., Duca, J. S., Lesburg, C. A., Ogas, P., Gray, K., Nale, L., Mannarino, A. F., Prongay, A. J., and Le, H. V. (2009) Thermodynamics of nucleotide and inhibitor binding to wild-type and ispinesib-resistant forms of human KSP Biochemistry 48, 11045-11055
21. Kayne, F. J. (1973) The Enzymes, Vol. 8, Academic Press, New York.
22. Waldron, T. T. and Murphy, K. P. (2003) Stabilization of proteins by ligand binding: Application to drug screening and determination of unfolding energetics Biochemistry 42, 5058-5064
23. Brandts, J. F. and Lin, L. N. (1990) Study of strong ultratight protein interactions using differential scanning calorimetry Biochemistry 29, 6927-6940
24. Mayhood, T. W. and Windsor, W. T. (2005) Ligand binding affinity determined by temperature-dependent circular dichroism: Cyclin-dependent kinase 2 inhibitors Anal. Biochem. 345, 187-197
25. Lad, L., Luo, L., Carson, J. D., Wood, K. W., Hartman, J. J., Copeland, R. A., and Sakowicz, R. (2008) Mechanism of inhibition of human KSP by ispinesib Biochemistry 47, 3576-3585
26. 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 ion strength on KSP inhibition Biochemistry 43, 15258-15266
27. Knight, S. D. and Parrish, C. A. (2008) Recent progress in the identification and clinical evaluation of inhibitors of the mitotic kinesin KSP Curr. Top. Med. Chem. 8, 888-904
28. Rickert, K. W., Schaber, M., Torrent, M., Neilson, L. A., Tasber, E. S., Garbaccio, R., Coleman, P. J., Harvey, D., Zhang, Y., Yang, Y., Marshall, G., Lee, L., Walsh, E. S., Hamilton, K., and Buser, C. A. (2008) Discovery and biochemical characterization of selective ATP competitive inhibitors of the human mitotic kinesin KSP Arch. Biochem. Biophys. 469, 220-231
29. Pantoliano, M. L., Petrella, E. C., Kwasnoski, J. D., Lobanov, V. S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B. A., Lane, P., and Salemme, F. R. (2001) High-density miniaturized thermal shift assays as a general strategy for drug discovery J. Biomol. Screen. 6, 429-440
30. Berenbaum, M. C. (1989) What is synergy? Pharmacol. Rev. 41, 93-141
31. Tallerida, R. J. (2000) Drug Synergism and Dose-Effect Data Analysis, Chapman & Hall/CRC, Boca Raton, FL.