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Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486 [D. M. B., P. A. M., J. Z., E. L., C. W.] and Department of Natural Products Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065 [O. H., L. K., J. L., M. G.]
Tubulin polymerization into microtubules is a dynamic process, with the equilibrium between growth and shrinkage being essential for many cellular processes. The antineoplastic agent taxol hyperstabilizes polymerized microtubules, leading to mitotic arrest and cytotoxicity in proliferating cells. Using a sensitive filtration-calorimetric assay to detect microtubule nucleating activity, we have identified epotheliones A and B as compounds that possess all the biological effects of taxol both in vitro and in cultured cells. The epothilones are equipotent and exhibit kinetics similar to taxol in inducing tubulin polymerization into microtubules in vitro (filtration, light scattering, sedimentation, and electron microscopy) and in producing enhanced microtubule stability and bundling in cultured cells. Furthermore, these 16-membered macrolides are competitive inhibitors of [3H]taxol binding, exhibiting a 50% inhibitory concentration almost identical to that of taxol in displacement competition assays. Epothilones also cause cell cycle arrest at the G2-M transition leading to cytotoxicity, similar to taxol. In contrast to taxol, epothilones retain a much greater toxicity against P-glycoprotein-expressing multiple drug resistant cells. Epothilones, therefore, represent a novel structural class of compounds, the first to be described since the original discovery of taxol, which not only mimic the biological effects of taxol but also appear to bind to the same microtubule-binding site as taxol.
1 Present address: Astral, Inc., San Diego, CA 92121.
2 Present address: Alliance Pharmaceutical Corp., San Diego, CA 92121.
Received 1/11/95. Accepted 4/ 5/95.
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O. Smaletz, M. Galsky, H. I. Scher, A. DeLaCruz, S. F. Slovin, M. J. Morris, D. B. Solit, U. Davar, L. Schwartz, and W. K. Kelly Pilot study of epothilone B analog (BMS-247550) and estramustine phosphate in patients with progressive metastatic prostate cancer following castration Ann. Onc., October 1, 2003; 14(10): 1518 - 1524. [Abstract] [Full Text] [PDF]
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K. Kamath and M. A. Jordan Suppression of Microtubule Dynamics by Epothilone B Is Associated with Mitotic Arrest Cancer Res., September 15, 2003; 63(18): 6026 - 6031. [Abstract] [Full Text] [PDF]
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K. Pietras, M. Stumm, M. Hubert, E. Buchdunger, K. Rubin, C.-H. Heldin, P. McSheehy, M. Wartmann, and A. Ostman STI571 Enhances the Therapeutic Index of Epothilone B by a Tumor-selective Increase of Drug Uptake Clin. Cancer Res., September 1, 2003; 9(10): 3779 - 3787. [Abstract] [Full Text] [PDF]
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T. L. Tinley, D. A. Randall-Hlubek, R. M. Leal, E. M. Jackson, J. W. Cessac, J. C. Quada Jr., T. K. Hemscheidt, and S. L. Mooberry Taccalonolides E and A: Plant-derived Steroids with Microtubule-stabilizing Activity Cancer Res., June 15, 2003; 63(12): 3211 - 3220. [Abstract] [Full Text] [PDF]
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J. Abraham, M. Agrawal, S. Bakke, A. Rutt, M. Edgerly, F. M. Balis, B. Widemann, L. Davis, B. Damle, D. Sonnichsen, et al. Phase I Trial and Pharmacokinetic Study of BMS-247550, an Epothilone B Analog, Administered Intravenously on a Daily Schedule for Five Days J. Clin. Oncol., May 1, 2003; 21(9): 1866 - 1873. [Abstract] [Full Text] [PDF]
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J. F. Diaz, I. Barasoain, and J. M. Andreu Fast Kinetics of Taxol Binding to Microtubules. EFFECTS OF SOLUTION VARIABLES AND MICROTUBULE-ASSOCIATED PROTEINS J. Biol. Chem., February 28, 2003; 278(10): 8407 - 8419. [Abstract] [Full Text] [PDF]
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S. Wittmann, P. Bali, S. Donapaty, R. Nimmanapalli, F. Guo, H. Yamaguchi, M. Huang, R. Jove, H. G. Wang, and K. Bhalla Flavopiridol Down-Regulates Antiapoptotic Proteins and Sensitizes Human Breast Cancer Cells to Epothilone B-induced Apoptosis Cancer Res., January 1, 2003; 63(1): 93 - 99. [Abstract] [Full Text] [PDF]
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 B. Julien and S. Shah Heterologous Expression of Epothilone Biosynthetic Genes in Myxococcus xanthus Antimicrob. Agents Chemother., September 1, 2002; 46(9): 2772 - 2778. [Abstract] [Full Text] [PDF]
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Y.-H. Ling, J.-D. Jiang, J. F. Holland, and R. Perez-Soler Arsenic Trioxide Produces Polymerization of Microtubules and Mitotic Arrest before Apoptosis in Human Tumor Cell Lines Mol. Pharmacol., September 1, 2002; 62(3): 529 - 538. [Abstract] [Full Text] [PDF]
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L. E. Broker, C. Huisman, C. G. Ferreira, J. A. Rodriguez, F. A. E. Kruyt, and G. Giaccone Late Activation of Apoptotic Pathways Plays a Negligible Role in Mediating the Cytotoxic Effects of Discodermolide and Epothilone B in Non-Small Cell Lung Cancer Cells Cancer Res., July 15, 2002; 62(14): 4081 - 4088. [Abstract] [Full Text] [PDF]
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H. M. McDaid, S. Mani, H.-J. Shen, F. Muggia, D. Sonnichsen, and S. B. Horwitz Validation of the Pharmacodynamics of BMS-247550, an Analogue of Epothilone B, during a Phase I Clinical Study Clin. Cancer Res., July 1, 2002; 8(7): 2035 - 2043. [Abstract] [Full Text] [PDF]
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T. Beckers, T. Reissmann, M. Schmidt, A. M. Burger, H. H. Fiebig, U. Vanhoefer, H. Pongratz, H. Hufsky, J. Hockemeyer, M. Frieser, et al. 2-Aroylindoles, a Novel Class of Potent, Orally Active Small Molecule Tubulin Inhibitors Cancer Res., June 1, 2002; 62(11): 3113 - 3119. [Abstract] [Full Text] [PDF]
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K. A. Hood, L. M. West, B. Rouwe, P. T. Northcote, M. V. Berridge, St. J. Wakefield, and J. H. Miller Peloruside A, a Novel Antimitotic Agent with Paclitaxel-like Microtubule- stabilizing Activity Cancer Res., June 1, 2002; 62(12): 3356 - 3360. [Abstract] [Full Text] [PDF]
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J.-G. Chen and S. B. Horwitz Differential Mitotic Responses to Microtubule-stabilizing and -destabilizing Drugs Cancer Res., April 1, 2002; 62(7): 1935 - 1938. [Abstract] [Full Text] [PDF]
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H. Yamaguchi, S. R. Paranawithana, M. W. Lee, Z. Huang, K. N. Bhalla, and H.-G. Wang Epothilone B Analogue (BMS-247550)-mediated Cytotoxicity through Induction of Bax Conformational Change in Human Breast Cancer Cells Cancer Res., January 1, 2002; 62(2): 466 - 471. [Abstract] [Full Text] [PDF]
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L. He, C.-P. Huang Yang, and S. B. Horwitz Mutations in {beta}-Tubulin Map to Domains Involved in Regulation of Microtubule Stability in Epothilone- resistant Cell Lines Mol. Cancer Ther., November 1, 2001; 1(1): 3 - 10. [Abstract] [Full Text] [PDF]
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R. B. Lichtner, A. Rotgeri, T. Bunte, B. Buchmann, J. Hoffmann, W. Schwede, W. Skuballa, and U. Klar Subcellular distribution of epothilones in human tumor cells PNAS, September 13, 2001; (2001) 171023398. [Abstract] [Full Text] [PDF]
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T.-C. Chou, O. A. O'Connor, W. P. Tong, Y. Guan, Z.-G. Zhang, S. J. Stachel, C. Lee, and S. J. Danishefsky The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: Curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice PNAS, July 3, 2001; 98(14): 8113 - 8118. [Abstract] [Full Text] [PDF]
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F. Y. F. Lee, R. Borzilleri, C. R. Fairchild, S.-H. Kim, B. H. Long, C. Reventos-Suarez, G. D. Vite, W. C. Rose, and R. A. Kramer BMS-247550: A Novel Epothilone Analog with a Mode of Action Similar to Paclitaxel but Possessing Superior Antitumor Efficacy Clin. Cancer Res., May 1, 2001; 7(5): 1429 - 1437. [Abstract] [Full Text]
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G. Bacher, B. Nickel, P. Emig, U. Vanhoefer, S. Seeber, A. Shandra, T. Klenner, and T. Beckers D-24851, a Novel Synthetic Microtubule Inhibitor, Exerts Curative Antitumoral Activity in Vivo, Shows Efficacy toward Multidrug-resistant Tumor Cells, and Lacks Neurotoxicity Cancer Res., January 1, 2001; 61(1): 392 - 399. [Abstract] [Full Text]
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M. Roberge, B. Cinel, H. J. Anderson, L. Lim, X. Jiang, L. Xu, C. M. Bigg, M. T. Kelly, and R. J. Andersen Cell-based Screen for Antimitotic Agents and Identification of Analogues of Rhizoxin, Eleutherobin, and Paclitaxel in Natural Extracts Cancer Res., September 1, 2000; 60(18): 5052 - 5058. [Abstract] [Full Text]
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L. A. Martello, H. M. McDaid, D. L. Regl, C.-P. H. Yang, D. Meng, T. R. R. Pettus, M. D. Kaufman, H. Arimoto, S. J. Danishefsky, A. B. Smith III, et al. Taxol and Discodermolide Represent a Synergistic Drug Combination in Human Carcinoma Cell Lines Clin. Cancer Res., May 1, 2000; 6(5): 1978 - 1987. [Abstract] [Full Text]
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C. Combeau, J. Provost, F. Lancelin, Y. Tournoux, F. Prod'homme, F. Herman, F. Lavelle, J. Leboul, and M. Vuilhorgne RPR112378 and RPR115781: Two Representatives of a New Family of Microtubule Assembly Inhibitors Mol. Pharmacol., March 1, 2000; 57(3): 553 - 563. [Abstract] [Full Text]
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 L. M. Leoni, E. Hamel, D. Genini, H. Shih, C. J. Carrera, H. B. Cottam, and D. A. Carson Indanocine, a Microtubule-Binding Indanone and a Selective Inducer of Apoptosis in Multidrug-Resistant Cancer Cells J Natl Cancer Inst, February 2, 2000; 92(3): 217 - 224. [Abstract] [Full Text] [PDF]
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L. Tang, S. Shah, L. Chung, J. Carney, L. Katz, C. Khosla, and B. Julien Cloning and Heterologous Expression of the Epothilone Gene Cluster Science, January 28, 2000; 287(5453): 640 - 642. [Abstract] [Full Text]
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B. Silakowski, H. U. Schairer, H. Ehret, B. Kunze, S. Weinig, G. Nordsiek, P. Brandt, H. Blocker, G. Hofle, S. Beyer, et al. New Lessons for Combinatorial Biosynthesis from Myxobacteria. THE MYXOTHIAZOL BIOSYNTHETIC GENE CLUSTER OF Stigmatella aurantiaca DW4/3-1 J. Biol. Chem., December 24, 1999; 274(52): 37391 - 37399. [Abstract] [Full Text] [PDF]
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I. Ojima, S. Chakravarty, T. Inoue, S. Lin, L. He, S. B. Horwitz, S. D. Kuduk, and S. J. Danishefsky A common pharmacophore for cytotoxic natural products that stabilize microtubules PNAS, April 13, 1999; 96(8): 4256 - 4261. [Abstract] [Full Text] [PDF]
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C. Dumontet and B. I. Sikic Mechanisms of Action of and Resistance to Antitubulin Agents: Microtubule Dynamics, Drug Transport, and Cell Death J. Clin. Oncol., March 1, 1999; 17(3): 1061 - 1061. [Abstract] [Full Text] [PDF]
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S. L. Mooberry, G. Tien, A. H. Hernandez, A. Plubrukarn, and B. S. Davidson Laulimalide and Isolaulimalide, New Paclitaxel-Like Microtubule-Stabilizing Agents Cancer Res., February 1, 1999; 59(3): 653 - 660. [Abstract] [Full Text] [PDF]
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T.-C. Chou, X.-G. Zhang, C. R. Harris, S. D. Kuduk, A. Balog, K. A. Savin, J. R. Bertino, and S. J. Danishefsky Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel PNAS, December 22, 1998; 95(26): 15798 - 15802. [Abstract] [Full Text] [PDF]
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S. C. Sinha, C. F. Barbas III, and R. A. Lerner The antibody catalysis route to the total synthesis of epothilones PNAS, December 8, 1998; 95(25): 14603 - 14608. [Abstract] [Full Text] [PDF]
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T.-C. Chou, X.-G. Zhang, A. Balog, D.-S. Su, D. Meng, K. Savin, J. R. Bertino, and S. J. Danishefsky Desoxyepothilone B: An efficacious microtubule-targeted antitumor agent with a promising in vivo profile relative to epothilone B PNAS, August 4, 1998; 95(16): 9642 - 9647. [Abstract] [Full Text] [PDF]
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P. J. Moos and F. A. Fitzpatrick Taxane-mediated gene induction is independent of microtubule stabilization: Induction of transcription regulators and enzymes that modulate inflammation and apoptosis PNAS, March 31, 1998; 95(7): 3896 - 3901. [Abstract] [Full Text] [PDF]
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M. M. Moasser, L. Sepp-Lorenzino, N. E. Kohl, A. Oliff, A. Balog, D.-S. Su, S. J. Danishefsky, and N. Rosen Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones PNAS, February 17, 1998; 95(4): 1369 - 1374. [Abstract] [Full Text] [PDF]
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