Recent progress in the identification and clinical evaluation of inhibitors of the mitotic kinesin KSP

Current Topics in Medicinal Chemistry

Volumn 8, Issue 10, 2008, Pages 888-904

  Knight, Steven D ^a   Parrish, Cynthia A ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

Cancer; Eg5; Inhibitor; Kinesin; Kinesin spindle protein; KSP

Indexed keywords

2 PIPERIDEINE DERIVATIVE; 2,3 DIHYDRO[1,3,4]OXADIAZOLE DERIVATIVE; 2,3 DIHYDRO[1,3,4]THIADIAZOLE DERIVATIVE; 3,5 DIARYL 4,5 DIHYDROPYRAZOLE DERIVATIVE; 4,5 DIHYDROPYRAZOLE; ANTHRACYCLINE DERIVATIVE; ANTINEOPLASTIC AGENT; ARRY 520; AZD 4877; CAPECITABINE; CARBOPLATIN; DIHYDROPYRAZOLE; DIHYDROPYRAZOLOBENZOXAZINE; DIHYDROPYRROLE DERIVATIVE; DOCETAXEL; EMD 534085; HEXAHYDROCYCLOPENTAQUINOLINE DERIVATIVE; HEXAHYDROFUROQUINOLINE; HEXAHYDROPYRANOQUINOLINE; ISPINESIB; KINESIN; KINESIN SPINDLE PROTEIN; KINESIN SPINDLE PROTEIN INHIBITOR; LY 2523355; MK 0731; PROTEIN INHIBITOR; SB 743921; TAXANE DERIVATIVE; TETRAHYDRODIOXOLOQUINOLINE DERIVATIVE; UNINDEXED DRUG;

ADVANCED CANCER; ALLOSTERISM; BONE MARROW SUPPRESSION; CLINICAL TRIAL; DRUG BINDING; DRUG DOSE ESCALATION; DRUG DOSE REGIMEN; DRUG STRUCTURE; HUMAN; MALIGNANT NEOPLASTIC DISEASE; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; NEUTROPENIA; NEUTROPHIL COUNT; NONHUMAN; PERIPHERAL NEUROPATHY; PROTEIN TARGETING; REVIEW; SIDE EFFECT; SOLID TUMOR;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; KINESIN; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NEOPLASMS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 47249083435     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802608784911626     Document Type: Review

References (137)

1. Wood, K. W.; Cornwell, W. D.; Jackson, J. R. Past and future of the mitotic spindle as an oncology target. Curr. Opin. Pharmacol. 2001, 1, 370-377.
2. Wood, K. W.; Bergnes, G. Mitotic Kinesin Inhibitors as Novel Anti-cancer Agents. Annu. Rep. Med. Chem. 2004, 39, 173-183.
3. Sawin, K. E.; LeGuellec, K.; Philippe, M.; Mitchison, T. J. Mitotic spindle organization by a plus-end-directed microtubule motor. Nature 1992, 359, 540-543.
4. Blangy, A.; Lane, H. A.; d'Herin, P.; Harper, M.; Kress, M.; Nigg, E. A. Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 1995, 83, 1159-1169.
5. Jackson, J. R.; Patrick, D. R.; Dar, M. M.; Huang, P. S. Targeted anti-mitotic therapies: Can we improve on tubulin agents? Nature Rev. Cancer 2007, 7, 107-117.
6. Rowinsky, E. K.; Eisenhauer, E. A.; Chaudhry, V.; Arbuck, S. G.; Donehower, R. C. Clinical toxicities encountered with paclitaxel (Taxol). Semin. Oncol. 1993, 20, 1-15.
7. Quasthoff, S.; Hartung, H. P. Chemotherapy-induced peripheral neuropathy. J. Neurol. 2002, 249, 9-17.
8. 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.; Wood, K. W. Antitumor Activity of a Kinesin Inhibitor. Cancer Res. 2004, 64, 3276-3280.
9. See company websites.
10. www.clinicaltrials.gov.
11. www.pharmaprojects.com.
12. Coleman, P. J.; Fraley, M. E. Inhibitors of the mitotic kinesin spindle protein. Expert Opin. Ther. Pat. 2004, 14, 1659-1667.
13. Jiang, C.; You, Q.; Li, Z.; Guo, Q. Kinesin spindle protein inhibitors as anticancer agents. Expert Opin. Ther. Pat. 2006, 16, 1517-1532.
14. Duhl, D. M.; Renhowe, P. A. Inhibitors of kinesin motor proteins - research and clinical progress. Curr. Opin. Drug Discov. Dev. 2005, 8, 431-436.
15. Bergnes, G.; Brejc, K.; Belmont, L. Mitotic Kinesins: Prospects for Antimitotic Drug Discovery. Curr. Topics Med. Chem. 2005, 5, 127-145.
16. Howard, J. Mechanics of Motor Proteins and the Cytoskeleton; Sinauer Associates, Inc.: Sunderland, MA, 2001.
17. Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.; Mitchison, T. J. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 1999, 286, 971-974.
18. Maliga, Z.; Kapoor, T. M.; Mitchison, T. J. Evidence that Monastrol Is an Allosteric Inhibitor of the Mitotic Kinesin Eg5. Chem. Biol. 2002, 9, 989-996.
19. Yan, Y.; Sardana, V.; Xu, B.; Homnick, C.; Halczenko, W.; Buser, C. A.; Schaber, M.; Hartman, G. D.; Huber, H. E.; Kuo, L. C. Inhibition of a Mitotic Motor Protein: Where, How, and Conformational Consequences. J. Mol. Biol. 2004, 335, 547-554.
20. www.proweb.org/kinesin/.
21. DeLano, W. L. The PyMOL Molecular Graphics System; DeLano Scientific: Palo Alto, CA, 2002.
22. Johnson, R. K.; McCabe, F. L.; Cauder, E.; Innlow, L.; Whitacre, M.; Winkler, J. D.; Bergnes, G.; Feng, B.; Smith, W. W.; Morgans, D.; Wood, K.; Jackson, J. R. SB-715992, a Potent and Selective Inhibitor of KSP Mitotic Kinesin, Demonstrates Broad-spectrum Activity in Advanced Murine Tumors and Human Tumor Xenografts. Presented at the 2002 AACR Annual Meeting, San Francisco, CA, April 2002; Poster 1335.
23. Gonzales, P.; Bienek, A.; Boehme, M.; Rivali C.; Roth, S.; Wynne, H.; Piazza, G.; Weitman, S.; Wood, K.; Crompton, A.; Moody, R.; Schauer, S.; Feng, B.; Bergnes, G.; Sigal, N.; Morgans, D. Breadth of Anti-tumor Activity of CK0238273 (SB-715992), a Novel Inhibitor of the Mitotic Kinesin KSP. Presented at the 2002 AACR Annual Meeting, San Francisco, CA, April 2002; Poster 1337.
24. Bergnes, G.; Ha, E.; Yao, B.; Smith, W. W.; Tochimoto, T.; Lewis, E. R.; Lee, Y. Y.; Moody, R.; Turincio, R. A.; Finer, J. T.; Wood, K. W.; Sakowicz, R.; Crompton, A. M.; Chabala, J. C.; Morgans, D. J., Jr.; Sigal, N. H.; Sabry, J. H. Mitotic Kinesin-Targeted Antitumor Agents: Discovery, Lead Optimization and Anti-Tumor Activity of a Series of Novel Quinazolinones as Inhibitors of Kinesin Spindle Protein (KSP). Presented at the 2002 AACR Annual Meeting, San Francisco, CA, April 2002; Poster 3648.
25. 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.-Y.; Huang, P.; Wood, K. W.; Belmont, L.; Lee, Y.; Bergnes, G.; Anderson, R.; Brejc, K.; Sakowicz, R. A Resistance Mechanism for the KSP Inhibitor Ispinesib Implicates Point Mutations in the Compound Binding Site. Presented at the 17th AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Philadelphia, PA, Nov 2005; Poster C207.
26. Lad, L.; Luo, L.; Carson, J. D.; Wood, K. W.; Hartman, J. J.; Copeland, R. A.; Sakowicz, R. Mechanism of Inhibition of Human KSP by Ispinesib. Biochemistry 2008, 47, 3578-3585.
27. Chu, Q.; Holen, K. D.; Rowinsky, E. K.; Wilding, G.; Volkman, J. L.; Orr, J. B.; Williams, D. D.; Hodge, J. P.; Kerfoot, C. A.; Sabry, J. A phase I study of novel kinesin spindle protein (KSP) inhibtor, SB-715992 administered intravenously once every 21 days Presented at the 40th ASCO Annual Meeting, New Orleans, LA, June 2004; Poster 2078.
28. Burris, I. H.; LoRusso, P.; Jones, S.; Guthrie, T.; Orr, J. B.; Williams, D. D.; Hodge, J. P.; Bush, M.; Sabry, J. Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV days 1, 8, 15 q 28 days. Presented at the 40th ASCO Annual Meeting, New Orleans, LA, June 2004; Poster 2004.
29. Jones, S.; Plummer, E.; Burris, H.; Razak, A.; Meluch, A.; Bowen, C.; Williams, D.; Vasist, L.; Hodge, J,; Dar, M.; Calvert, A. Phase I study of ispinesib in combination with carboplatin in patients with advanced solid tumors. Presented at the 42nd ASCO Annual Meeting, Atlanta, GA, June 2006; Poster 2027.
30. Blagden, S.; Seebaran, G.; Molife, R.; Payne, M.; Reid, A.; Protheroe, A.; Kathman, S.; Williams, D.; Bowen, C.; Hodge, J.; Dar, M.; de Bono, J.; Middleton, M. Phase I study of ispinesib (SB-715992) in combination with docetaxel in patients with advanced solid tumors. Presented at the 17th AACR-NIH-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Philadelphia, PA, Nov 17, 2005; Poster C80.
31. Blagden, S. P.; Molife, R. R.; Seebaran, A.; Payne, M.; Reid, A. H. M.; Protheroe, A. S.; Vasist, L. S.; Williams, D. D.; Bowen, C.; Kathman, S. J.; Hodge, J. P.; Dar, M. M.; de Bono, J. S.; Middleton, M. R. A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours. Br. J. Cancer 2008, 98, 894-899.
32. Calvo, E.; Chu, Q.; Till, E.; Rowinsky, E.; Patnaik, A.; Takimoto, C.; Kathman, S.; Williams, D.; Bowen, C.; Hodge, J.; Dar, M.; Tolcher, A. Phase I study of ispinesib (SB-715992) in combination with capecitabine in patients with advanced solid tumors. Presented at the 17th AACR-NIH-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Philadelphia, PA, Nov 17, 2005; Poster C85.
33. Knox, J. J.; Gill, S.; Synold, T. W.; Biagi, J. J.; Mejor, P.; Feld, R.; Cripps, C.; Wainman, N.; Eisenhauer, E.; Seymour, L. A phase II and pharmacokinetic study of SB-715992, in patients with metastatic hepatocellular carcinoma: A study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG IND.168). Invest. New Drugs 2008, published online Jan 15, 2008 (doi: 10.1007/ s10637-007-9103-2).
34. Lee, C. W.; Bélanger, K.; Rao, S. C.; Petrella, T. M.; Tozer, R. G.; Wood, L.; Savage, K. J.; Eisenhauer, E. A.; Synold, T. W.; Wainman, N.; Seymour, L. A phase II study of ispinesib (SB-715992) in patients with metastatic or recurrent malignant melanoma: A National Cancer Institute of Canada Clinical Trials Group trial. Invest. New Drugs 2008, published online Oct 26, 2007 (doi:10.1007/ s10637-007-9097-9).
35. Tang, P. A.; Siu, L. L.; Chen, E. X.; Hotte, S. J.; Chia, S.; Schwarz, J. K.; Pond, G. R.; Johnson, C.; Colevas, A. D.; Synold, T. W.; Vasist, L. S.; Winquist, E. Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck. Invest. New Drugs, 2008, published online Nov 24, 2007 (doi: 10.1007/ s10637-007-9098-8).
36. Miller, K.; Ng, C.; Ang, P.; Brufsky, A. M.; Lees, S. C.; Dees, E. C.; Piccart, M.; Verrill, M.; Wardley, A.; Loftiss, J.; Yeoh, S.; Hodge, J.; Williams, D.; Dar, M.; Ho, P. T. C. Phase II, open label study of SB-715992 (Ispinesib) in subjects with advanced or metastatic breast cancer. Presented at the 28th Annual San Antonio Breast Symposium, San Antonio, TX, Dec 2005; Poster 1089.
37. www.cytokinetics.com.
38. Holen, K. D.; Belani, C. P.; Wilding, G.; Ramalingam, S.; Volkman, J. L.; Ramanathan, R. K.; Bowen, C. J.; Williams, D. D.; Dar, M. M.; Ho, P. T. Phase I study to determine tolerability and pharmacokinetics (PK) of SB-743921, a novel kinesin spindle protein (KSP) inhibitor. Presented at the 2005 ASCO Annual Meeting, Orlando FL, May 2005; Abstract 2010.
39. O'Connor, O. A.; Goy, A.; Orlowski, R. Z.; Hainsworth, J.; Leonard, J. P.; Afanasyev, B.; Osmanor, D.; Reyno, L. M.; Chen, M. M.;.Escandon, R. D. A Phase I-II Study to Determine the Safety, Pharmacokinetics and Potential Efficacy of the Kinesin Spindle Protein (KSP) Inhibitor SB-743921 on Days 1 and 15 of a 28 Day Schedule in Patients with Non-Hodgkin's or Hodgkin's Lymphoma. Presented at the American Hematology Society Annual Meeting, Atlanta, GA, Dec 2007; Poster 2556.
40. Morgans, D. J. C.; Knight, S. D.; Newlander, K. A.; Dhanak, D.; Zhou, H.-J.; Adams, N. D. Compounds, Methods, and Compositions. WO2003094839A2, May 9, 2002.
41. McDonald, A.; Lu, P.-P.; Bergnes, G.; Morgans, D. J., Jr.; Dhanak, D.; Knight, S. D. 3-(Aminoalkyl)-2H-isoquinolin-1-one derivatives, pharmaceutical compositions containing them, and methods of their use as KSP kinesin inhibitors for the treatment of cancer. WO2003106426A1, June 14, 2002.
42. McDonald, A.; Morgans, D. J., Jr.; Bergnes, G.; Dhanak, D.; Knight, S. D. KSP kinesin-modulating compounds, compositions and methods for treatment of cellular proliferative diseases. WO2004006865A2, July 17, 2002.
43. McDonald, A.; Zhou, H.-J. Compounds, compositions and methods for treatment of cellular proliferative diseases. WO2004024086A2, Sept 13, 2002.
44. Bergnes, G.; Qian, X.; Morgans, D. J., Jr.; Knight, S. D.; Dhanak, D. 1,2,4-Triazol-5-ones as inhibitors of mitotic kinesin KSP. WO2004032840A2, Oct 11, 2002.
45. Zhou, H.-J.; McDonald, A.; Bergnes, G.; Morgans, D. J., Jr.; Chabala, J. C.; Knight, S. D.; Dhanak, D. Preparation of pyrimidinones for treating cellular proliferative diseases by modulating the activity of KSP. WO2004064741A2, Jan 17, 2003.
46. McDonald, A.; Bergnes, G.; Feng, B.; Morgans, D. J., Jr.; Knight, S. D.; Newlander, K. A.; Dhanak, D.; Brook, C. S. Preparation of chromones as KSP kinesin inhibitors. WO2003088903, Oct 30, 2003.
47. Bergnes, G. Pyrido[2,3-d]pyrimidin-4-one derivatives for treating cellular proliferative diseases and disorders by modulating the activity of KSP. WO2005046588, May 26, 2005.
48. Fraley, M. E.; Garbaccio, R. M. Preparation of cyclopenta(d) pyrimidinones as mitotic kinesin inhibitors for the treatment of cancer. WO2003049678A2, Dec 6, 2001.
49. Fraley, M. E.; Hartman, G. D.; Hoffman, W. F. Mitotic Kinesin Inhibitors. WO2003049679, Dec 6, 2001.
50. Coleman, P. J.; Fraley, M. E.; Hoffman, W. F. Preparation of 2-aminomethyl azaquinazolinones as mitotic KSP kinesin inhibitors for treating cellular proliferative diseases. WO2004039774A2, May 23, 2002.
51. Fraley, M. E.; Hartman, G. D.; Hoffman, W. F. Preparation of thienopyrimidines as mitotic kinesin inhibitors for the treatment of cancer. WO2003050064 A2, June 19, 2003.
52. Fraley, M. E.; Hartman, G. D. Preparation of furopyrimidinones as mitotic kinesin inhibitors for treatment of cancer. WO2003050122A2, June 19, 2003.
53. Wang, W.; Constantine, R.; Lagniton, L. Mitotic Kinesin Inhibitors. US2005228002, April 6, 2005.
54. Boyce, R. S.; Guo, H.; Mendenhall, K. G.; Walter, A. O.; Wang, W.; Xia, Y. Preparation of indole and benzimidazole derivatives as kinesin spindle protein (KSP) inhibitors for the treatment of cancer. US2006084687, April 20, 2006.
55. Barsanti, P. A.; Xia, Y.; Wang, W.; Mendenhall, K. G.; Lagniton, L. M.; Ramurthy, S.; Phillips, M. C.; Subramanian, S.; Boyce, R.; Brammeier, N. M.; Constantine, R.; Duhl, D.; Walter, A. O.; Abrams, T. J.; Renhowe, P. A. Substituted imidazole compounds as KSP inhibitors. US20070037853, Aug 9, 2006.
56. Lombardo, L. J.; Bhide, R. S.; Kim, K. S.; Lu, S. Pyrrolotriazinone compounds and their use to treat disease. WO2003099286A1, May 21, 2002.
57. Kim, K. S. Quinoxaline compounds and methods of using them. US2005176717, Feb 1, 2005.
58. Aguila, B.; Block, M. H.; Davies, A.; Ezhuthachan, J.; Filla, S.; Luke, R. W.; Pontz, T.; Theoclitou, M.-E.; Zheng, X. Novel fused heterocycles and uses thereof. WO2004078758, March 7, 2003.
59. www.mskcc.org/mskcc/html/2270.cfm?IRBNO=07-052.
60. Wang, W.; Lagniton, L. M.; Constantine, R. N.; Burger, M. T. Heteroryl-fused pyrimidinyl compounds as anticancer agents. WO2004111058, May 30, 2003.
61. Wang, W.; Constantine, R. N.; Lagniton, L. M.; Pecchi, S.; Burger, M. T.; Desai, M. C. Pyridino[1,2-a]pyrimidin-4-one compounds as anticancer agents. WO2004113335, June 20, 2003.
62. Bergnes, G.; Smith, W. W.; Yao, B.; Morgans, D. J., Jr.; McDonald, A. Preparation of qninazolinone-like derivatives to treat cellular proliferative diseases. WO2004009036A2, July 23, 2002.
63. Bergnes, G.; Morgans, D. J. Jr. Heterocyclic-substituted quinazolinones preparation for treating cellular proliferative diseases. WO2004034972A2, Sept 30, 2002.
64. Fraley, M. E.; Hoffman, W. F. Preparation of quinazolinone mitotic kinesin inhibitors for treating cancer. WO2003039460A2, Nov 7, 2001.
65. Feng, B.; Bergnes, G.; Morgans, D. J. C.; Dhanak, D.; Knight, S. D.; Darcy, M. G. 2-(1-(Imidazol-1-yl)alkyl)-3H-quinazolin-4-one derivatives, pharmaceutical compositions containing them, and methods of their use as KSP kinesin inhibitors for the treatment of cellular proliferative diseases. WO2003097053A1, May 9, 2002.
66. Bergnes, G.; Dhanak, D.; Knight, S. D.; Lu, P.-P.; Morgans, D. J., Jr.; Newlander, K. A. Preparation of oxodiazepanylquinazolinones as modulators of KSP kinesin activity for treatment of proliferative disease. WO2004055008A1, Dec 13, 2002.
67. Cox, C. D.; Breslin, M. J.; Mariano, B. J.; Coleman, P. J.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Huber, H. E.; Kohl, N. E.; Torrent, M.; Yan, Y.; Kuo, L. C.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part 1: The discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of the mitotic kinesin KSP. Bioorg. Med. Chem. Lett. 2005, 15, 2041-2045.
68. Fraley, M. E.; Garbaccio, R. M.; Arrington, K. L.; Hoffman, W. F.; Tasber, E. S.; Coleman, P. J.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Fernandes, C.; Schaber, M. D.; Lobell, R. B.; Tao, W.; South, V. J.; Yan, Y.; Kuo, L. C.; Prueksaritanont, T.; Shu, C.; Torrent, M.; Heimbrook, D. C.; Kohl, N. E.; Huber, H. E.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part 2: The design, synthesis, and characterization of 2,4-diaryl-2,5-dihydropyrrole inhibitors of the mitotic kinesin KSP. Bioorg. Med. Chem. Lett. 2006, 16, 1775-1779.
69. Garbaccio, R. M.; Fraley, M. E.; Tasber, E. S.; Olson, C. M.; Hoffman, W. F.; Arrington, K. L.; Torrent, M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Schaber, M. D.; Fernandes, C.; Lobell, R. B.; Tao, W.; South, V. J.; Yan, Y.; Kuo, L. C.; Prueksaritanont, T.; Slaughter, D. E.; Shu, C.; Heimbrook, D. C.; Kohl, N. E.; Huber, H. E.; Hartman G. D. Kinesin spindle protein (KSP) inhibitors. Part 3: Synthesis and evaluation of phenolic 2,4-diaryl-2,5 -dihydropyrroles with reduced hERG binding and employment of a phosphate prodrug strategy for aqueous solubility. Bioorg. Med. Chem. Lett. 2006, 16, 1780-1783.
70. 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. D.; 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.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl -4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP. Bioorg. Med. Chem. Lett. 2006, 16, 3175-3179.
71. Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Coleman, P. J.; Garbaccio, R. M.; Fraley, M. E.; Zrada, M. M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Tao, W.; Abrams, M. T.; South, V. J.; Huber, H. E.; Kohl, N. E.; Hartman G. D. Kinesin spindle protein (KSP) inhibitors, Part V: Discovery of 2-propylamino -2,4-diaryl-2,5-hydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein. Bioorg. Med. Chem. Lett. 2007, 17, 2697-2702.
72. Coleman, P. J.; Schreier, J. D.; Cox, C. D.; Fraley, M. E.; Garbaccio, R. M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, B.; Rickert K.; Tao, W.; Diehl, R. E.; South, V. J.; Davide, J. P.; Kohl, N. E.; Yan, Y.; Kuo, L.; Prueksaritanont, T.; Li, C.; Mahan, E. A.; Fernandez-Metzler, C.; Salata, J. J.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part 6: Design and Synthesis of 3,5-diaryl-4,5-dihydropyrazole amides as potent inhibitors of the mitotic kinesin KSP. Bioorg. Med. Chem. Lett. 2007, 17, 5390-5395.
73. Garbaccio, R. M.; Tasber, E. S.; Neilson, L. A.; Coleman, P. J.; Fraley, M. E.; Olson, C.; Bergman, J.; Torrent, M.; Buser, C. A.; Rickert, K.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Tao, W.; South, V. J.; Diehl, R. E.; Davide, J. P.; Yan, Y.; Kuo, L. C.; Li, C.; Prueksaritanont, T.; Fernandez-Metzler, C.; Mahan, E. A.; Slaughter, D. E.; Salata, J. J.; Kohl, N. E.; Huber, H. E.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part 7: Design and Synthesis of 3,3-disubstituted dihydropyrazolobenoxazines as potent inhibitors of the mitotic kinesin KSP. Bioorg. Med. Chem. Lett. 2007, 17, 5671-5676.
74. Roecker, A. J.; Coleman, P. J.; Mercer, S. P.; Schreier, J. D.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Tao, W.; Diehl, R. E.; South, V. J.; Davide, J. P.; Kohl, N. E.; Yan, Y.; Kuo, L. C.; Li, C.; Fernandez-Metzler, C.; Mahan, E. A.; Prueksaritanont, T.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part 8: Design and Synthesis of 1,4-diaryl-4,5-dihydropyrazoles as potent inhibitors of the mitotic kinesin KSP. Bioorg. Med. Chem. Lett. 2007, 17, 5677-5682.
75. Tao, W.; South, V. J.; Zhang, Y.; Davide, J. P.; Farrell, L.; Kohl, N. E.; Sepp-Lorenzino, L.; Lobell, R. B. Introduction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell 2005, 8, 49-59.
76. Tao, W.; South, V. J.; Diehl, R. E.; Davide, J. P.; Sepp-Lorenzino, L.; Fraley, M. E.; Arrington, K. L.; Lobell, R. B. An inhibitor of the kinesin spindle protein activates the intrinsic apoptotic pathway independently of p53 and de novo protein synthesis. Mol. Cell. Biol. 2007, 27, 689-698.
77. Javadi, G.; Karady, S.; Maeda, K.; Miller, R. A.; Szumigala, R. H. A process for the preparation of 2,2-disubstituted pyrroles. WO2005102996, Nov 3, 2005.
78. Stein, M. N.; Rubin, E. H.; Scott, P. D.; Fernandez, R.; Agrawal, N. G.; Hsu, K.; Walker, A.; Holen, K.; Wilding, G. Phase I clinical and pharmacokinetic (PK) trial of the kinesin spindle protein (KSP) inhibitor MK-0731 in cancer patients. Presented at the 42nd ASCO Annual Meeting, Atlanta, GA, June 2006; Abstract 2001.
79. Stein, M. N.; Tan, A.; Taber, K.; Fernandez, R.; Agrawal, N. G.; Vandendries, E.; Hsu, K.; Walker, A.; Holen, K.; Wilding, G. Phase I clinical and pharmacokinetic (PK) trial of the kinesin spindle protein (KSP) inhibitor MK-0731 in patients with solid tumors. Presented at the 43rd ASCO Annual Meeting, Chicago, IL, June 2007; Abstract 2548.
80. www.merck.com/finance/pipeline.swf.
81. Fraley, M. E.; Garbaccio, R. M. Mitotic Kinesin Inhibitors. WO2004058148, Dec 20, 2002.
82. Fraley, M. E.; Garbaccio, R. M.; Olson, C. M.; Tasber, E. S. Mitotic Kinesin Inhibitors. WO2004058700, Dec 20, 2002.
83. Hans, J.; Wallace, E. M.; Zhao, Q.; Lyssikatos, J. P.; Aicher, T.; Laird, E.; Robinson, J.; Allen, S. Preparation of oxadiazole and thiadiazole derivatives as mitotic kinesin inhibitors. WO2006044825, April 27, 2006.
84. Hans, J.; Wallace, E. M.; Zhao, Q.; Allen, S.; Laird, E.; Lyssikatos, J. P.; Robinson, J. E.; Corrette, C. P.; Delisle, R. K. Mitotic kinesin inhibitors and methods of use thereof. US2006247178, May 1, 2006.
85. www.arraybiopharma.com.
86. Woessner, R.; Corrette, C.; Allen, S.; Hans, J.; Zhao, Q.; Aicher, T.; Lyssikatos, J.; Robinson, J.; Poch, G.; Hayter, L.; Cox, A.; Lee, P.; Winkler, J.; Koch, K.; Wallace, E. ARRY-520, a KSP Inhibitor with Efficacy and Pharmacodynamic Activity in Animal Models of Solid Tumors. Presented at the 2007 AACR National Meeting, Los Angeles, CA, April 2007; Poster 1433.
87. Murakata, C.; Amishiro, N.; Ino, Y.; Yamamoto, J.; Atsumi, T.; Nakai, R.; Nakano, T. Preparation of thiadiazoline derivatives as M-phase kinesin Eg5 inhibitors for treatment of tumor. WO2005035512, Oct 8, 2004.
88. Murakata, C.; Kato, K.; Yamamoto, J.; Nakai, R.; Okamoto, S.; Ino, Y.; Kitamura, Y.; Saitoh, T.; Katsuhira, T. Agent for treatment of solid tumor. WO2006101102A1, Sept 28, 2006.
89. http://investor.lilly.com/downloads/elli27858.pdf.
90. www.mmcca.org/patients/clinicaltrials.htm.
91. Schiemann, K.; Anzali, S.; Drosdat, H.; Emde, U.; Finsinger, D.; Gleitz, J.; Hock, B.; Reubold, H.; Zenke, F. Preparation of heteroaryl substituted tetrahydroquinolines as inhibitors of Eg5 proteins. WO2005063735A1, July 14, 2005.
92. Schiemann, K.; Bruge, D.; Buchstaller, H.; Finsinger, D.; Staehle, W.; Amendt, C.; Emde, U.; Zenke, F. Preparation of fused tetrahydroquinolines as anticancer drugs. WO2006002726A1, Jan 12, 2006.
93. Staehle, W.; Bruge, D.; Schiemann, K.; Finsinger, D.; Buchstaller, H.; Zenke, F.; Amendt, C. Preparation of tetrahydroquinoline derivatives for use in the treatment of tumors. DE102005027169A1, Dec 14, 2006.
94. Schiemann, K.; Bruge, D.; Buchstaller, H.; Emde, U.; Finsinger, D.; Amendt, C.; Zenke, F. Preparation of tetrahydroquinolines for use in the treatment of tumors. DE102005027168A1, Dec 14, 2006.
95. Finsinger, D.; Zenke, F.; Amendt, C.; Schiemann, K.; Emde, U.; Knöchel, T.; Bomke, J.; Gleitz, J.; Wilm, C.; Meyring, M.; Osswald, M.; Funk, J. Discovery, synthesis and characterization of hexahydropyranoquinolines as a novel class of selective inhibitors of the mitotic kinesin Eg5. Presented at the 97th annual meeting of the American Association for Cancer Research (AACR), Washington, DC, April 2006; 5713.
96. Merck Serono Fall 2007 Presentation Roadshow, www.merck.de/servlet/PB/ menu/1101280/index.html.
97. Schiemann, K.; Emde, U.; Schlueter, T.; Saal, C.; Maiwald, M. Preparation of polymorphic forms of pyranoquinolines for treatment of proliferative diseases. WO2007147480A2, Dec 27, 2007.
98. Hotha, S.; Yarrow, J. C.; Yang, J. G.; Garrett, S.; Renduchintala, K. V.; Mayer, T. U.; Kapoor, T. M. HR22C16: A potent small-molecule probe for the dynamics of cell division. Angew. Chem. Int. Ed. Engl. 2003, 42, 2379-2382.
99. Tarby, C. M.; Kaltenbach, R. F.; Huynh, T.; Pudzianowski, A.; Shen, H.; Ortega-Nanos, M.; Sheriff, S.; Newitt, J. A.; McDonnell, P. A.; Burford, N.; Fairchild, C. R.; Vaccaro, W.; Chen, Z.; Borzilleri, R. M.; Naglich, J.; Lombardo, L. J.; Gottardis, M.; Trainor, G. L.; Roussell, D. L. Inhibitors of human mitotic kinesin Eg5: Characterization of the 4-phenyl-tetrahydroisoquinoline lead series. Bioorg. Med. Chem. Lett. 2006, 16, 2095-2100.
100. Sunder-Plassmann, N.; Sarli, V.; Gartner, M.; Utz, M.; Seiler, J.; Huemmer, S.; Mayer, T. U.; Surrey, T.; Giannis, A. Synthesis and biological evaluation of new tetrahydro-b-carbolines as inhibitors of the mitotic kinesin Eg5. Bioorg. Med. Chem. 2005, 13, 6094-6111.
101. Wang, W.; Ni, Z.; Barsanti, P.; Pecchi, S.; Xia, Y.; Brammeier, N.; Treutle, M.; Jazan, E.; Wayman, K.; Dibble, D.; Cheng, J. Preparation of tetrahydrocarboline derivatives as anticancer agents. WO2005070930A2, Aug 4, 2005.
102. Vennemann, M.; Baer, T.; Groegor, G.; Braunger, J.; Gimmnich, P.; Maier, T.; Rothfels, H. Preparation of benzothienopyridine derivatives as inhibitors of Eg5 kinesin. WO2006018435A1, Feb 23, 2006.
103. Vennemann, M.; Baer, T.; Braunger, J.; Zimmermann, A.; Gekeler, V. Preparation of indolopyridines as Eg5 kinesin modulators. WO2007096393A1, Aug 30, 2007.
104. Vennemann, M.; Baer, T.; Braunger, J.; Zimmermann, A.; Gekeler, V. Preparation of indolopyridines as Eg5 kinesin modulators. WO2007096395A1, Aug 30, 2007.
105. Pinkerton, A. B.; Lee, T. T.; Hoffman, T. Z.; Wang, Y.; Kahraman, M.; Cook, T. G.; Severance, D.; Gahman, T. C.; Noble, S. A.; Shiau, A. K.; Davis, R. L. Synthesis and SAR of thiophene containing kinesin spindle protein (KSP) inhibitors. Bioorg. Med. Chem. Lett., 2007, 17, 3562-3569.
106. Kimball, D. S.; Lombardo, L. J.; Rawlins, D. B.; Xiao, H.; Schmidt, R. J.; Williams, D. K. Novel cyano-substituted dihydropyrimidine compounds and their use to treat diseases. WO2002079149A2, Oct 10, 2002.
107. Lombardo, L. J.; Wu, L. I. Cyano-substituted dihydropyrimidine compounds and their use to treat diseases. WO2002079169A1, Oct 10, 2002.
108. Gartner, M.; Sunder-Plassmann, N.; Seiler, J.; Utz, M.; Vernos, I.; Surrey, T.; Giannis, A. Development and Biological Evaluation of Potent and Specific Inhibitors of Mitotic Kinesin Eg5. ChemBioChem 2005, 6, 1173-1177.
109. Sarli, V.; Huemmer, S.; Sunder-Plassmann, N.; Mayer, T. U.; Giannis, A. Synthesis and biological evaluation of novel Eg5 inhibitors. ChemBioChem 2005, 6, 2005-2013.
110. Surrey, T.; Athanassios, G.; Vernos, I.; Gartner, M.; Sunder-Plassmann N.; Vasiliki, S.; Mayer, T.; Huemmer, S. Preparation of hydroxyphenylquinazolinethiones as inhibitors of mitotic kinesin Eg5. WO2006048308A1, May 11, 2006.
111. Mazitschek, R.; Tallarico, J. A.; Maliga, Z.; Mitchison, T. J. Preparation of bicyclic dihydropyrimidines, constrained analogs of monastrol, as kinesin inhibitors for treating neoplasm. WO2006074293A2, July 13, 2006.
112. Lopez, R.; Rousseau, B.; Kozielsky, F.; Skoufias, D. A.; DeBonis, S. Dihydropyrimidine derivatives, their preparation, and their use for the treatment of cancer and other diseases. WO2006097617A2, Sept 21, 2006.
113. Klein, E.; DeBonis, S.; Thiede, B.; Skoufias, D. A.; Kozielski, F.; Lebeau, L. New chemical tools for investigating human mitotic kinesin Eg5. Bioorg. Med. Chem. 2007, 15, 6474-6488.
114. DeBonis, S.; Skoufias, D. A.; Lebeau, L.; Robin, G.; Margolis, R.; Wade, R. H.; Kozielski, F. In vitro screening for inhibitors of the human mitotic kinesin, Eg5, with antimitotic and antitumor activity. Mol. Cancer Ther. 2004, 3, 1079-1090.
115. Brier, S.; Lemaire, D.; DeBonis, S.; Forest, E.; Kozielski, F. Identification of the Protein Binding Region of S-Trityl-L-cysteine, a New Potent Inhibitor of the Mitotic Kinesin Eg5. Biochemistry 2004, 43, 13072-13082.
116. Brier, S.; Lemaire, D.; DeBonis, S.; Forest, E.; Kozielski, F. Molecular Dissection of the Inhibitor Binding Pocket of Mitotic Kinesin Eg5 Reveals Mutants that Confer Resistance to Antimitotic Agents. J. Mol. Biol. 2006, 360, 360-376.
117. Skoufias, D. A.; DeBonis, S.; Saoudi, Y.; Lebeau, L.; Crevel, L; Cross, R.; Wade, R. H.; Hackney, D.; Kozielski, F. S-Trityl-L-cysteine Is a Reversible, Tight Binding Inhibitor of the Human Kinesin Eg5 That Specifically Blocks Mitotic Progression. J. Biol. Chem. 2006, 281, 17559-17569.
118. DeBonis, S.; Skoufias, D. A.; Indorato, R.; Liger, F.; Marquet, B.; Laggner, C.; Joseph, B.; Kozielski, F. Structure-Activity Relationship of S-Trityl-L-Cysteine Analogues as Inhibitors of the Human Mitotic Kinesin Eg5. J. Med. Chem. 2008, 51, 1115-1125.
119. Ogo, N.; Oishi, S.; Matsuno, K.; Sawada, J.; Fujii, N.; Asai, A, Synthesis and biological evaluation of L-cysteine derivatives as mitotic kinesin Eg5 inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 3921-3924.
120. Parrish, C. A.; Adams, N. D.; Auger, K. R.; Burgess, J. L.; Carson, J. D.; Chaudhari, A. M.; Copeland, R. A.; Diamond, M. A.; Donatelli, C. A.; Duffy, K. J.; Faucette, 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.; Sutton, D.; Wood, K. W.; Zhang, S.; Zimmerman, M. N.; Dhanak, D. Novel ATP-Competitive Kinesin Spindle Protein Inhibitors. J. Med. Chem. 2007, 50, 4939-4952.
121. Luo, L.; Parrish, C. A.; Nevins, 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.; Dbanak D.; Copeland, R. A.; Auger, K. R. ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism. Nat. Chem. Biol. 2007, 3, 722-726.
122. 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.; Buser, C. A. Discovery and biochemical characterization of selective ATP competitive inhibitors of the human mitotic kinesin KSP. Arch. Biochem. Biophys. 2008, 469, 220-231.
123. www.combinatorx.com.
124. Lee, M. S.; Johansen, L.; Zhang, Y.; Wilson, A.; Keegan, M.; Avery, W.; Elliott, P.; Borisy, A. A.; Keith, C. T. The Novel Combination of Chlorpromazine and Pentamidine Exerts Synergistic Antiproliferative Effects through Dual Mitotic Action. Cancer Res. 2007, 67, 11359-11367.
125. Pathak, M. K.; Dhawan, D.; Lindner, D. J.; Borden, E. C.; Farver, C.; Yi, T. Pentamidine is an inhibitor of PRL phosphatases with anticancer activity. Mol. Cancer Ther. 2002, 1, 1255-1264.
126. Wang, J.; Kirby, C. E.; Herbst, R. The tyrosine phosphatase PRL-1 localizes to the endoplasmic reticulum and the mitotic spindle and is required for normal mitotsis. J. Biol. Chem. 2002, 277, 46659-46668.
127. Von Hoff, D. D.; Gordon, M.; Turner, J.; White, E.; Nichols, M. J.; Elliott, P. J.; Mendelson, D. A phase I study with CRx-026, a novel dual action agent, in patients with advanced solid tumors. Presented at the 41st ASCO Annual Meeting, Orlando, FL, May 2005; Poster 3073.
128. Tagat, J. R.; Guzi, T. J.; Labroli, M.; Poker, C.; Kerekes, A. D.; Yu, T.; Tsui, H.; Shih, N.; Xiao, Y.; Paliwal, S. Preparation of thienoquinolines for inhibiting KSP kinesin activity. WO2006098962A1, Sept 21, 2006.
129. Tagat, J. R.; Guzi, T. J.; Labroli, M.; Poker, C.; Xiao, Y.; Kerekes, A. D.; Yu, T.; Paliwal, S.; Tsui, H.; Shih, N.; Mccombie, S. W.; Madison, V. S.; Lesburg, C. A.; Duca, J. S. Tetrahydrothieno[2,3-b]quinolines and related compounds and their preparation, pharmaceutical composition, and use for inhibiting KSP kinesin activity and treatment of proliferative diseases. WO2006098961A2, Sept 21, 2006.
130. Pinkerton, A. B.; Davis, R. L.; Hoffman, T. Z.; Herbert, M. R.; Kahraman, M.; Thayer, A. M. Preparation of [1,2,4]triazines as inhibitors of mitotic kinegin. WO2007011721A1, Jan 25, 2007.
131. Pinkerton, A. B.; Davis, R. L.; Hoffman, T. Z.; Herbert, M. R. Preparation of [1,2,4]triazines as inhibitors of mitotic kinesin. WO2007011759A2, Jan 25, 2007.
132. Pinkerton, A. B.; David, R. L. Preparation of nicotinamides as inhibitors of mitotic kinesin. WO2007011760A2, Jan 25, 2007.
133. Qian, X.; McDonald, A. I.; Zhou, H.; Ashcraft, L. W.; Yao, B.; Jiang, H.; Huang, J. K. C.; Wang, J.; Morgans, D. J., Jr.; Morgan, B. P.; Bergnes, G.; Dhanak, D.; Knight, S. D.; Adams, N. D.; Parrish, C. A. Preparation of amino acid-related compounds for treating cellular proliferative diseases. WO2005107762A2, Nov 17, 2005.
134. Qian, X; Bergnes, G.; Newlander, K. A.; Fitch, D.; Dhanak, D. Preparation of aromatic compounds as inhibitors of mitotic kinesins. WO2007056143A2, May 18, 2007.
135. Sutton, D.; Gilmartin, A. G.; Kusnierz, A.; Sung, C.; Luo, L.; Carson, J. D.; Laquerre, S. G.; Cornwell, W. D.; King, A. G.; Knight, S. D.; Dhanak, D.; Bergnes, G.; Qian, X; Chua, P.; Wood, K. W.; Huang, P. S.; Weber, B. L.; Copeland, R. A.; Jackson, J. R. A potent and selective inhibitor of the mitotic kinesin CENP-E (GSK923295A), demonstrates a novel mechanism of inhibiting tumor cell proliferation and shows activity against a broad panel of human tumor cell lines in vitro. Presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, San Francisco, CA, Oct 2007; Poster A111.
136. Lad, L.; Luo, L.; Wood, K.; Copeland, R. A.; Carson, J. D.; Sakowicz, R. Detailed biochemical analysis of the CENP-E inhibitor GSK923295A. Presented at the 2007 AACR Annual Meeting, Los Angeles, CA, April 16, 2007; Poster 3179.
137. Chua, P. R.; Desai, R.; Schauer, S. P.; Cornwell, W. D.; Gilmartin, A. G.; Sutton, D.; Wood, K. W. Differential Response of Tumor Cell Lines to Inhibition of the Mitotic Checkpoint Regulator and Mitotic Kinesin, CENP-E, Presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, San Francisco, CA, Oct 2007; Poster A114.