Advertisement

Drugs in R & D

, Volume 9, Issue 1, pp 1–10 | Cite as

Discovery and Development of the Epothilones

A Novel Class of Antineoplastic Drugs
Review Article

Abstract

The epothilones are a novel class of antineoplastic agents possessing antitubulin activity. The compounds were originally identified as secondary metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum. Two major compounds, epothilone A and epothilone B, were purified from the S. cellulosum strain So ce90 and their structures were identified as 16-member macrolides. Initial screening with these compounds revealed a very narrow and selective antifungal activity against the zygomycete, Mucor hiemalis. In addition, strong cytotoxic activity against eukaryotic cells, mouse L929 fibroblasts and human T-24 bladder carcinoma cells was observed. Subsequent studies revealed that epothilones induce tubulin polymerization and enhance microtubule stability. Epothilone-induced stabilisation of microtubules was shown to cause arrest at the G2/M transition of the cell cycle and apoptosis. The compounds are active against cancer cells that have developed resistance to taxanes as a result of acquisition of β-tubulin overexpression or mutations and against multidrug-resistant cells that overexpress P-glycoprotein or multidrug resistance-associated protein. Thus, epothilones represent a new class of antimicrotubule agents with low susceptibility to key tumour resistance mechanisms.

More recently, a range of synthetic and semisynthetic epothilone analogues have been produced to further improve the adverse effect profile (or therapeutic window) and to maximize pharmacokinetic and antitumour properties. Various epothilone analogues have demonstrated activity against many tumour types in preclinical studies and several compounds have been and still are being evaluated in clinical trials. This article reviews the identification and early molecular characterization of the epothilones, which has provided insight into the mode of action of these novel antitumour agents in vivo.

Keywords

Vinca Alkaloid Ixabepilone Tubulin Polymerization Epothilones Tubulin Isotype 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

Research work related to this manuscript was supported by the Helmholtz Centre for Infection Research. The authors gratefully acknowledge the editorial assistance of Roy Garcia, PhD in the preparation of this article and thank Bristol-Myers Squibb for their support in providing access to information on ixabepilone. The authors are consultants for Bristol-Myers Squibb.

References

  1. 1.
    Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol 2005; 205 (2): 275–92PubMedCrossRefGoogle Scholar
  2. 2.
    Moscow J, Morrow CS, Cowan KH. Drug resistance and its clinical circumvention. In: Holland JF, Frei III E, editors. Cancer medicine. Toronto: BC Decker, 2003Google Scholar
  3. 3.
    Leonessa F, Clarke R. ATP binding cassette transporters and drug resistance in breast cancer. Endocr Relat Cancer 2003; 10 (1): 43–73PubMedCrossRefGoogle Scholar
  4. 4.
    Endicott JA, Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 1989; 58: 137–71PubMedCrossRefGoogle Scholar
  5. 5.
    Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993; 62: 385–427PubMedCrossRefGoogle Scholar
  6. 6.
    Luqmani YA. Mechanisms of drug resistance in cancer chemotherapy. Med Princ Pract 2005; 14 Suppl. 1: 35–48PubMedCrossRefGoogle Scholar
  7. 7.
    Lavelle F. What’s new about new tubulin/microtubule-binding agents? Exp Opin Invest Drugs 1995; 4 (8): 771–5CrossRefGoogle Scholar
  8. 8.
    Reichenbach H. Order VIII Myxococcales Tchan, Pochon and Prévot. 1948, 398AL. In: Brenner DJ, Krieg NR, Stanley JT, et al., editors. Bergey’s manual of systematic bacteriology, 2nd ed. Vol. 2, Part C. New York (NY): Springer, 2005: 1059–144Google Scholar
  9. 9.
    Dworkin M. Recent advances in the social and developmental biology of the myxobacteria. Microbiol Rev 1996; 60 (1): 70–102PubMedGoogle Scholar
  10. 10.
    Höfle G, Reichenbach H. Biosynthetic potential of the myxobacteria. In: Kuhn W, Fiedler H, editors. Sekundärmetabolismus bei Mikroorganismen. Tübingen: Attempto Verlag, 1995: 61–78Google Scholar
  11. 11.
    Reichenbach H, Höfle G. Myxobacteria as producers of secondary metabolites. In: Grabley S, Thierecke R, editors. Drug discovery from nature. Berlin: Springer, 1999: 79Google Scholar
  12. 12.
    Reichenbach H, Höfle G. Biologically active secondary metabolites from myxobacteria. Biotechnol Adv 1993; 11 (2): 219–77PubMedCrossRefGoogle Scholar
  13. 13.
    Gerth K, Bedorf N, Höfle G, et al. Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (myxobacteria): production, physico-chemical and biological properties. J Antibiot (Tokyo) 1996; 49 (6): 560–3CrossRefGoogle Scholar
  14. 14.
    Höfle G, Bedorf N. German Patent No. DE413 8042, 1993Google Scholar
  15. 15.
    Niggemann J, Bedorf N, Flörke U, et al. Spirangien A and B, highly cytotoxic and antifungal spiroketals from the myxobacterium Sorangium cellulosum: isolation, structure elucidation and chemical modifications. Eur J Org Chem 2005; 23: 5013–8CrossRefGoogle Scholar
  16. 16.
    Höfle G, Bedorf N, Steinmetz H, et al. Epothilone A and B: novel 16-membered macrolides with cytotoxic activity. Isolation, crystal structure, and conformation in solution. Angew Chem Int Ed Engl 1996; 35 (13/14): 1567–9CrossRefGoogle Scholar
  17. 17.
    Gerth K, Steinmetz H, Höfle G, et al. Studies on the biosynthesis of epothilones: the PKS and epothilone C/D monooxygenase. J Antibiot (Tokyo) 2001; 54 (2): 144–8CrossRefGoogle Scholar
  18. 18.
    Gerth K, Steinmetz H, Höfle G, et al. Studies on the biosynthesis of epothilones: the biosynthetic origin of the carbon skeleton. J Antibiot (Tokyo) 2000; 53 (12): 1373–7CrossRefGoogle Scholar
  19. 19.
    Bollag DM, McQueney PA, Zhu J, et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 1995; 55 (11): 2325–33PubMedGoogle Scholar
  20. 20.
    Buey RM, Diaz JF, Andreu JM, et al. Interaction of epothilone analogs with the paclitaxel binding site: relationship between binding affinity, microtubule stabilization, and cytotoxicity. Chem Biol 2004; 11 (2): 225–36PubMedGoogle Scholar
  21. 21.
    Heinz DW, Schubert WD, Höfle G. Much anticipated: the bioactive conformation of epothilone and its binding to tubulin. Angew Chem Int Ed Engl 2005; 44 (9): 1298–301PubMedCrossRefGoogle Scholar
  22. 22.
    Bode CJ, Gupta Jr ML, Reiff EA, et al. Epothilone and paclitaxel: unexpected differences in promoting the assembly and stabilization of yeast microtubules. Biochemistry 2002; 41 (12): 3870–4PubMedCrossRefGoogle Scholar
  23. 23.
    Wartmann M, Altmann KH. The biology and medicinal chemistry of epothilones. Curr Med Chem Anti-Canc Agents 2002; 2 (1): 123–48Google Scholar
  24. 24.
    Owellen RJ, Hartke CA, Dickerson RM, et al. Inhibition of tubulin-microtubule polymerization by drugs of the vinca alkaloid class. Cancer Res 1976; 36 (4): 1499–502PubMedGoogle Scholar
  25. 25.
    Schiff PB, Horwitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci U S A 1980; 77 (3): 1561–5PubMedCrossRefGoogle Scholar
  26. 26.
    Arnal I, Wade RH. How does taxol stabilize microtubules? Curr Biol 1995; 5 (8): 900–8PubMedCrossRefGoogle Scholar
  27. 27.
    Gupta Jr ML, Bode CJ, Georg GI, et al. Understanding tubulin-Taxol interactions: mutations that impart Taxol binding to yeast tubulin. Proc Natl Acad Sci USA 2003; 100 (11): 6394–7PubMedCrossRefGoogle Scholar
  28. 28.
    Oakley BR. An abundance of tubulins. Trends Cell Biol 2000; 10 (12): 537–42PubMedCrossRefGoogle Scholar
  29. 29.
    Desai A, Mitchison TJ. Microtubule polymerization dynamics. Annu Rev Cell Dev Biol 1997; 13: 83–117PubMedCrossRefGoogle Scholar
  30. 30.
    Sharp DJ, Rogers GC, Scholey JM. Microtubule motors in mitosis. Nature 2000; 407: 41–7PubMedCrossRefGoogle Scholar
  31. 31.
    Lee FY, Borzilleri R, Fairchild CR, et al. BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 2001; 7 (5): 1429–37PubMedGoogle Scholar
  32. 32.
    Kowalski RJ, Giannakakou P, Hamel E. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol®). J Biol Chem 1997; 272 (4): 2534–41PubMedCrossRefGoogle Scholar
  33. 33.
    Kamath K, Jordan MA. Suppression of microtubule dynamics by epothilone B is associated with mitotic arrest. Cancer Res 2003; 63 (18): 6026–31PubMedGoogle Scholar
  34. 34.
    Verrills NM, Flemming CL, Liu M, et al. Microtubule alterations and mutations induced by desoxyepothilone B: implications for drug-target interactions. Chem Biol 2003; 10 (7): 597–607PubMedCrossRefGoogle Scholar
  35. 35.
    Yamaguchi H, Chen J, Bhalla K, et al. Regulation of Bax activation and apoptotic response to microtubule-damaging agents by p53 transcription-dependent and -independent pathways. J Biol Chem 2004; 279 (38): 39431–7PubMedCrossRefGoogle Scholar
  36. 36.
    Bhalla KN. Microtubule-targeted anticancer agents and apoptosis. Oncogene 2003; 22: 9075–86PubMedCrossRefGoogle Scholar
  37. 37.
    Verrills NM, Kavallaris M. Improving the targeting of tubulin-binding agents: lessons from drug resistance studies. Curr Pharm Des 2005; 11 (13): 1719–33PubMedCrossRefGoogle Scholar
  38. 38.
    Kamath K, Wilson L, Cabral F, et al. BetaIII-tubulin induces paclitaxel resistance in association with reduced effects on microtubule dynamic instability. J Biol Chem 2005; 280 (13): 12902–7PubMedCrossRefGoogle Scholar
  39. 39.
    Paradiso A, Mangia A, Chiriatti A, et al. Biomarkers predictive for clinical efficacy of taxol-based chemotherapy in advanced breast cancer. Ann Oncol 2005; 16 (4 Suppl.): iv14–9PubMedCrossRefGoogle Scholar
  40. 40.
    Seve P, Mackey J, Isaac S, et al. Class III beta-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel. Mol Cancer Ther 2005; 4 (12): 2001–7PubMedCrossRefGoogle Scholar
  41. 41.
    Ofir R, Seidman R, Rabinski T, et al. Taxol-induced apoptosis in human SKOV3 ovarian and MCF7 breast carcinoma cells is caspase-3 and caspase-9 independent. Cell Death Differ 2002; 9: 636–42PubMedCrossRefGoogle Scholar
  42. 42.
    Ahn HJ, Kim YS, Kim JU, et al. Mechanism of taxol-induced apoptosis in human SKOV3 ovarian carcinoma cells. J Cell Biochem 2004; 91: 1043–52PubMedCrossRefGoogle Scholar
  43. 43.
    Griffin D, Wittmann S, Guo F, et al. Molecular determinants of epothilone B derivative (BMS 247550) and Apo-2L/TRAIL-induced apoptosis of human ovarian cancer cells. Gynecol Oncol 2003 Apr; 89 (1): 37–47PubMedCrossRefGoogle Scholar
  44. 44.
    Guo F, Nimmanapalli R, Paranawithana S, et al. Ectopic over-expression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis. Blood 2002 May 1; 99 (9): 3419–26PubMedCrossRefGoogle Scholar
  45. 45.
    Uyar D, Takigawa N, Mekhail T, et al. Apoptotic pathways of epothilone BMS 310705. Gynecol Oncol 2003; 91: 173–8PubMedCrossRefGoogle Scholar
  46. 46.
    Wu KD, Cho YS, Katz J, et al. Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo. Proc Natl Acad Sci USA. 2005 Jul 26; 102 (30): 10640–5PubMedCrossRefGoogle Scholar
  47. 47.
    Wartmann M, Koppler J, Lartigot M. Epothilones A and B accumulate several-hundred fold inside cells [abstract 1362]. Proc Am Assoc Cancer Res 2000; 41: 213Google Scholar
  48. 48.
    Altmann KH. Epothilone B and its analogs: a new family of anticancer agents. Mini Rev Med Chem 2003; 3 (2): 149–58PubMedCrossRefGoogle Scholar
  49. 49.
    Su DS, Balog A, Meng D, et al. Structure-activity relationship of the epothilones and the first in vivo comparison with paclitaxel. Angew Chem Int Ed Engl 1997; 36 (19): 2093–6CrossRefGoogle Scholar
  50. 50.
    Chou TC, Zhang XG, Balog A, et al. Desoxyepothilone B: an efficacious microtubule-targeted antitumor agent with a promising in vivo profile relative to epothilone B. Proc Natl Acad Sci U S A 1998; 95 (16): 9642–7PubMedCrossRefGoogle Scholar
  51. 51.
    Rothermel J, Wartmann M, Chen T, et al. EPO906 (epothilone B): a promising novel microtubule stabilizer. Semin Oncol 2003; 30 (3 Suppl. 6): 51–5PubMedGoogle Scholar
  52. 52.
    Altmann KH, Wartmann M, O’Reilly T. Epothilones and related structures: a new class of microtubule inhibitors with potent in vivo antitumor activity. Biochim Biophys Acta 2000; 1470 (3): M79–91PubMedGoogle Scholar
  53. 53.
    Altmann KH. The chemistry and biology of epothilones: lead structures for the discovery of improved microtubule inhibitors. In: Liang XT, Fang WS, editors. Medicinal chemistry of bioactive natural products. Hoboken (NJ): Wiley, 2006: 1–34CrossRefGoogle Scholar
  54. 54.
    Jordan MA, Miller H, Ni L, et al. The Pat-21 breast cancer model derived from a patient with primary Taxol® resistance recapitulates the phenotype of its origin, has altered β-tubulin expression and is sensitive to ixabepilone [abstract]. Proc Amer Assoc Cancer Res 2006; 47: LB–280Google Scholar
  55. 55.
    Nicolaou KC, Sasmal PK, Rassias G, et al. Design, synthesis, and biological properties of highly potent epothilone B analogues. Angew Chem Int Ed Engl 2003; 42 (30): 3515–20PubMedCrossRefGoogle Scholar
  56. 56.
    Blum W, Aichholz R, Ramstein P, et al. In vivo metabolism of epothilone B in tumor-bearing nude mice: identification of three new epothilone B metabolites by capillary high-pressure liquid chromatography/mass spectrometry/tandem mass spectrometry. Rapid Commun Mass Spectrom 2001; 15 (1): 41–9PubMedCrossRefGoogle Scholar
  57. 57.
    Chou TC, O’Connor OA, Tong WP, et al. 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. Proc Natl Acad Sci U S A 2001; 98 (14): 8113–8PubMedCrossRefGoogle Scholar
  58. 58.
    Altmann KA, Bold G, Caravatti G, et al. Epothilones and their analogs: potential new weapons in the fight against cancer. Chimia 2000; 54: 612–21Google Scholar
  59. 59.
    Höfle G, Reichenbach H. Epothilone, a myxobacterial metabolite with promising antitumor activity. In: Cragg G, Kingston D, Newman D, editors. Anticancer agents from natural products. Boca Raton (FL): Taylor & Francis Group, 2005: 413–450Google Scholar
  60. 60.
    Vite G, Höfle G, Bifano M. The semisynthesis and preclinical evaluation of BMS-310705, an epothilone analog in clinical development [abstract]. 223rd Am Chem Soc Meeting; 2002; MEDI 18Google Scholar
  61. 61.
    Kolman A. BMS-310705 Bristol Myers Squibb/GBF. Curr Opin Invest Drugs 2004 Dec; 5 (12): 1292–7Google Scholar
  62. 62.
    Zhou Y, Zhong Z, Liu F. KOS-1584: a rationally designed epothilone D analog with improved potency and pharmacokinetic (PK) properties [abstract]. Proc Amer Assoc Cancer Res 2005; 46: 2535Google Scholar
  63. 63.
    Klar U, Buchmann B, Schwede W, et al. Total synthesis and antitumor activity of ZK-EPO: the first fully synthetic epothilone in clinical development. Angew Chem Int Ed Engl 2006; 45 (47): 7942–8CrossRefGoogle Scholar
  64. 64.
    Chou TC, Dong H, Zhang X, et al. Therapeutic cure against human tumor xenografts in nude mice by a microtubule stabilization agent, fludelone, via parenteral or oral route. Cancer Res 2005; 65 (20): 9445–54PubMedCrossRefGoogle Scholar
  65. 65.
    Dilea C, Wartmann M, Maira SM. A PK-PD dose optimization strategy for the microtubule stabilizing agent ABJ879 [abstract]. Proc Amer Assoc Cancer Res 2004; 45: 5132Google Scholar
  66. 66.
    Wartmann M, Loretan J, Reuter R. Preclinical pharmacological profile of ABJ879, a novel epothilone B analog with potent and protracted anti-tumor activity [abstract]. Proc Amer Assoc Cancer Res 2004; 45: 5440Google Scholar
  67. 67.
    Wu KD, Cho YS, Katz J, et al. Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo. Proc Natl Acad Sci U S A 2005; 102 (30): 10640–5PubMedCrossRefGoogle Scholar
  68. 68.
    Goodin S, Kane MP, Rubin EH. Epothilones: mechanism of action and biologic activity. J Clin Oncol 2004 May 15; 22 (10): 2015–25PubMedCrossRefGoogle Scholar
  69. 69.
    Spriggs DR, Dupont J, Pezzulli S, et al. KOS-862 (epothilone D): phase 1 dose escalating and pharmacokinetic (PK) study in patients (pts) with advanced malignancies [abstract]. ECCO 2003; 12: 547Google Scholar
  70. 70.
    Kuppens IELM. Current state of the art of new tubulin inhibitors in the clinic. Curr Clin Pharm 2006; 1: 57–70CrossRefGoogle Scholar
  71. 71.
    Cortes J, Baselga J. Targeting the microtubules in breast cancer beyond taxanes: the epothilones. Oncologist 2007 Mar; 12 (3): 271–80PubMedCrossRefGoogle Scholar
  72. 72.
    Larkin JM, Kaye SB. Epothilones in the treatment of cancer. Expert Opin Investig Drugs 2006 Jun; 15 (6): 691–702PubMedCrossRefGoogle Scholar
  73. 73.
    Lee JJ, Swain SM. Development of novel chemotherapeutic agents to evade the mechanisms of multidrug resistance (MDR). Semin Oncol 2005 Dec; 32 (6 Suppl. 7): S22–6PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  1. 1.Helmholtz-Zentrum für InfektionsforschungBraunschweigGermany

Personalised recommendations