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Eribulin Mesylate

Description of Eribulin mesylate: Eribulin mesylate is the mesylate salt of a synthetic analogue of halichondrin B, a substance derived from a marine sponge (Lissodendoryx sp.) with antineoplastic activity. Eribulin binds to the vinca domain of tubulin and inhibits the polymerization of tubulin and the assembly of microtubules, resulting in inhibition of mitotic spindle assembly, induction of cell cycle arrest at G2/M phase, and, potentially, tumor regression. On November 15, 2010, FDA granted approval for eribulin mesylate (Halaven  Injection, Eisai Inc.) for the treatment of patients with metastatic breast cancer who have previously received an anthracycline and a taxane in either the adjuvant or metastatic setting, and at least two chemotherapeutic regimens for the treatment of metastatic disease.  Halaven is a non-taxane, microtubule dynamics inhibitor. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).  

Current developer: Eisai Inc.

Eribulin was previously known as E7389 (and before that, ER-086526), and also carries the US NCI designation NSC-707389. Eribulin is currently being investigated by Eisai Co. for the third-line treatment of advanced breast cancer in patients who have been previously treated with anthracyclines, taxanes and capecitabine, as well as a variety of other solid tumors, including non-small cell lung cancer, prostate cancer and sarcoma. Structurally, eribulin is a fully synthetic macrocyclic ketone analogue of the marine sponge natural product halichondrin B, a potent mitotic inhibitor with a unique mechanism of action found in the Halichondria genus of sponges.  Eribulin is a mechanistically-unique inhibitor of microtubule dynamics, exerting its anticancer effects by triggering apoptosis of cancer cells following prolonged mitotic blockage. see: http://en.wikipedia.org/wiki/Eribulin.

 According to wikipedia, Halichondrin B (its chemical structure was shown in the following) is a naturally-occurring compound originally isolated from the marine sponge Halichondria okadai by Hirata and Uemura in 1986.  In the same report, these authors also reported the exquisite anticancer activity of halichondrin B against murine cancer cells both in culture and in in vivo studies. Halichondrin B was highly prioritized for development as a novel anticancer therapeutic by the United States National Cancer Institute and, in 1991, was the original test case for identification of mechanism of action (in this case, tubulin-targeted mitotic inhibitor) by NCI's now famous but then-brand new "60-cell line screen". The complete chemical synthesis of halichondrin B, a large (MW = 1,110) polyether macrolide, was achieved by Yoshito Kishi and colleagues at Harvard University in 1992,[3] an achievement that ultimately enabled the discovery and development of the structurally-simplified and pharmaceutically-optimized analog eribulin (E7389, ER-086526, NSC-707389).  Eribulin was approved by the U.S. Food and Drug Administration on November 15, 2010, to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline- and taxane-based chemotherapies.  Eribulin is marketed by Eisai Co. under the tradename Halaven. (source: http://en.wikipedia.org/wiki/Halichondrin_B).

Photo of Halichondria okadai (copied from http://www.futurity.org/health-medicine/sea-sponge-drug-battles-breast-cancer/).

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7: Dubbelman AC, Rosing H, Thijssen B, Lucas L, Copalu W, Wanders J, Schellens JH, Beijnen JH. Validation of high-performance liquid chromatography-tandem mass spectrometry assays for the quantification of eribulin (E7389) in various biological matrices. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 May 1;879(15-16):1149-55. Epub 2011 Mar 17. PubMed PMID: 21458392.

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11: Cortes J, Lorca R. Eribulin mesylate: a promising new antineoplastic agent for locally advanced or metastatic breast cancer. Future Oncol. 2011 Mar;7(3):355-64. Epub 2011 Mar 7. PubMed PMID: 21375468.

12: Huyck TK, Gradishar W, Manuguid F, Kirkpatrick P. Eribulin mesylate. Nat Rev Drug Discov. 2011 Mar;10(3):173-4. PubMed PMID: 21358731.

13: Narayan S, Carlson EM, Cheng H, Condon K, Du H, Eckley S, Hu Y, Jiang Y, Kumar V, Lewis BM, Saxton P, Schuck E, Seletsky BM, Tendyke K, Zhang H, Zheng W, Littlefield BA, Towle MJ, Yu MJ. Novel second generation analogs of eribulin. Part II: Orally available and active against resistant tumors in vivo. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1634-8. Epub 2011 Jan 25. PubMed PMID: 21324692.

14: Narayan S, Carlson EM, Cheng H, Condon K, Du H, Eckley S, Hu Y, Jiang Y, Kumar V, Lewis BM, Saxton P, Schuck E, Seletsky BM, Tendyke K, Zhang H, Zheng W, Littlefield BA, Towle MJ, Yu MJ. Novel second generation analogs of eribulin. Part III: Blood-brain barrier permeability and in vivo activity in a brain tumor model. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1639-43. Epub 2011 Jan 26. PubMed PMID: 21324687.

15: Narayan S, Carlson EM, Cheng H, Du H, Hu Y, Jiang Y, Lewis BM, Seletsky BM, Tendyke K, Zhang H, Zheng W, Littlefield BA, Towle MJ, Yu MJ. Novel second generation analogs of eribulin. Part I: Compounds containing a lipophilic C32 side chain overcome P-glycoprotein susceptibility. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1630-3. Epub 2011 Jan 31. PubMed PMID: 21324686.

16: Traynor K. Eribulin approved for advanced breast cancer. Am J Health Syst Pharm. 2011 Jan 1;68(1):6. PubMed PMID: 21164057.

17: Taur JS, DesJardins CS, Schuck EL, Wong YN. Interactions between the chemotherapeutic agent eribulin mesylate (E7389) and P-glycoprotein in CF-1 abcb1a-deficient mice and Caco-2 cells. Xenobiotica. 2011 Apr;41(4):320-6. Epub 2010 Dec 17. PubMed PMID: 21162698.

18: Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis BM, Kishi Y, Yu MJ, Littlefield BA. Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions. Cancer Res. 2011 Jan 15;71(2):496-505. Epub 2010 Dec 2. PubMed PMID: 21127197.

19: Gradishar WJ. The place for eribulin in the treatment of metastatic breast cancer. Curr Oncol Rep. 2011 Feb;13(1):11-6. Review. PubMed PMID: 21104168.

20: Mani S, Swami U. Eribulin mesilate, a halichondrin B analogue, in the treatment of breast cancer. Drugs Today (Barc). 2010 Sep;46(9):641-53. PubMed PMID: 20967296.

21: Morris PG. Advances in therapy: eribulin improves survival for metastatic breast cancer. Anticancer Drugs. 2010 Nov;21(10):885-9. Review. PubMed PMID: 20838209.

22: Cortes J, Vahdat L, Blum JL, Twelves C, Campone M, Roché H, Bachelot T, Awada A, Paridaens R, Goncalves A, Shuster DE, Wanders J, Fang F, Gurnani R, Richmond E, Cole PE, Ashworth S, Allison MA. Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2010 Sep 1;28(25):3922-8. Epub 2010 Aug 2. PubMed PMID: 20679609.

23: Cigler T, Vahdat LT. Eribulin mesylate for the treatment of breast cancer. Expert Opin Pharmacother. 2010 Jun;11(9):1587-93. Review. PubMed PMID: 20450446.

24: Twelves C, Cortes J, Vahdat LT, Wanders J, Akerele C, Kaufman PA. Phase III trials of eribulin mesylate (E7389) in extensively pretreated patients with locally recurrent or metastatic breast cancer. Clin Breast Cancer. 2010 Apr;10(2):160-3. PubMed PMID: 20299316.

25: Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA. Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry. 2010 Feb 16;49(6):1331-7. PubMed PMID: 20030375; PubMed Central PMCID: PMC2846717.

26: Arnold SM, Moon J, Williamson SK, Atkins JN, Ou SH, LeBlanc M, Urba SG. Phase II evaluation of eribulin mesylate (E7389, NSC 707389) in patients with metastatic or recurrent squamous cell carcinoma of the head and neck: Southwest Oncology Group trial S0618. Invest New Drugs. 2011 Apr;29(2):352-9. Epub 2009 Nov 25. PubMed PMID: 19937365; PubMed Central PMCID: PMC2892241.

27: Alday PH, Correia JJ. Macromolecular interaction of halichondrin B analogues eribulin (E7389) and ER-076349 with tubulin by analytical ultracentrifugation. Biochemistry. 2009 Aug 25;48(33):7927-38. PubMed PMID: 19586046.

28: Goel S, Mita AC, Mita M, Rowinsky EK, Chu QS, Wong N, Desjardins C, Fang F, Jansen M, Shuster DE, Mani S, Takimoto CH. A phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid malignancies. Clin Cancer Res. 2009 Jun 15;15(12):4207-12. Epub 2009 Jun 9. PubMed PMID: 19509177.

29: Tan AR, Rubin EH, Walton DC, Shuster DE, Wong YN, Fang F, Ashworth S, Rosen LS. Phase I study of eribulin mesylate administered once every 21 days in patients with advanced solid tumors. Clin Cancer Res. 2009 Jun 15;15(12):4213-9. Epub 2009 Jun 9. PubMed PMID: 19509146.

30: Jimeno A. Eribulin: rediscovering tubulin as an anticancer target. Clin Cancer Res. 2009 Jun 15;15(12):3903-5. Epub 2009 Jun 9. PubMed PMID: 19509144.

31: Vahdat LT, Pruitt B, Fabian CJ, Rivera RR, Smith DA, Tan-Chiu E, Wright J, Tan AR, Dacosta NA, Chuang E, Smith J, O'Shaughnessy J, Shuster DE, Meneses NL, Chandrawansa K, Fang F, Cole PE, Ashworth S, Blum JL. Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2009 Jun 20;27(18):2954-61. Epub 2009 Apr 6. PubMed PMID: 19349550.

32: Desjardins C, Saxton P, Lu SX, Li X, Rowbottom C, Wong YN. A high-performance liquid chromatography-tandem mass spectrometry method for the clinical combination study of carboplatin and anti-tumor agent eribulin mesylate (E7389) in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Nov 15;875(2):373-82. Epub 2008 Sep 19. PubMed PMID: 18835754.

33: Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther. 2008 Jul;7(7):2003-11. PubMed PMID: 18645010; PubMed Central PMCID: PMC2562299.

34: Zhang ZY, King BM, Pelletier RD, Wong YN. Delineation of the interactions between the chemotherapeutic agent eribulin mesylate (E7389) and human CYP3A4. Cancer Chemother Pharmacol. 2008 Sep;62(4):707-16. Epub 2008 Apr 23. PubMed PMID: 18431572.

35: Newman S. Eribulin, a simplified ketone analog of the tubulin inhibitor halichondrin B, for the potential treatment of cancer. Curr Opin Investig Drugs. 2007 Dec;8(12):1057-66. PubMed PMID: 18058576.