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Eribulin

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Eribulin
Clinical data
Trade namesHalaven
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa611007
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
  • 2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2',3'-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4H)-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.230.372 Edit this at Wikidata
Chemical and physical data
FormulaC40H59NO11
Molar mass729.908 g·mol−1
3D model (JSmol)
  • O=C1C[C@@H]2[C@H]([C@H](O[C@H]2C[C@H]3O[C@H](C[C@H](C3=C)C)CC[C@H]4C(C[C@@H](O4)CC[C@]5(O6)C[C@@H]([C@@H]7O5)O[C@H]([C@H]7O[C@]8(CC9)[H])[C@@H]6[C@@]8([H])O[C@H]9C1)=C)C[C@@H](CN)O)OC
  • InChI=1S/C41H61NO11/c1-20-12-26-7-9-29-21(2)13-25(46-29)6-5-11-41-18-34-37(52-41)38-39(51-34)40(53-41)36-30(50-38)10-8-27(48-36)14-23(43)15-28-32(17-31(47-26)22(20)3)49-33(35(28)45-4)16-24(44)19-42/h20,24-40,44H,2-3,5-19,42H2,1,4H3/t20-,24+,25+,26+,27-,28+,29+,30+,31-,32+,33-,34-,35-,36+,37+,38+,39-,40+,41+/m1/s1 checkY
  • Key:IGHZKAIPGTYWLF-FAXVPLPQSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Eribulin is an anticancer drug marketed by Eisai Co. under the trade name Halaven. Eribulin is also known as E7389 and ER-086526, and also carries the US NCI designation NSC-707389. It is used to treat certain patients with breast cancer and liposarcoma.

Intellectual Property

Currently there are 5 active patents in the United States that are associated with the Halaven drug application, N201532. The first one expires on June 16, 2019, the last one (USRE46965) expires on Jan 08, 2027.[1]

Approvals and indications

Breast cancer

The mesylate salt 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.[2] It was approved by Health Canada on December 14, 2011, for treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease.[3] Metastatic breast cancer impacts about 150,000 people in the USA, due to the patient population, Eisai was able to file and New Drug Application (NDA) under the orphan and rare disease designation.[4][5]

Liposarcoma

On January 28, 2016 the US FDA approved Halaven for the treatment of inoperable liposarcoma in patients who received prior chemotherapy that contained an anthracycline drug.[6] A phase III trial reported: With Halaven the median overall survival for patients with liposarcoma was 15.6 months, compared to 8.4 months for patients treated with dacarbazine.[6]

Clinical trials

Eribulin is also being investigated by Eisai Co. for use in a variety of other solid tumors, including non-small cell lung cancer, prostate cancer and sarcoma.[7]

Research and development

Two new eribulin based products are in the research and development phase; a liposomal formulation and antibody drug combination therapy, both are for the treatment of solid tumors. The liposomal formulation of eribulin, E7389 liposomal, is currently in Phase 1 clinical trials.[8] Preliminary in vivo experiments show a decrease in C(max) and a longer half-life with the liposomal formulation.[9] The drug antibody eribulin combination therapy is a joint venture between Eisai and Merck. The clinical trials combine eribulin and pembrolizumab, a PD-1 inhibitor, for the treatment of breast cancer and other advanced cancers.[10]

Structure and mechanism

Eribulin is a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B,[11][12] the parent molecule being a potent naturally occurring mitotic inhibitor with a unique mechanism of action found in the sponge genus Halichondria.[13][14]

Eribulin is a mechanistically unique inhibitor of microtubule dynamics,[15][16] binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.[17][18] Eribulin has both cytotoxic and non-cytotoxic mechanisms of action. Its cytotoxic effects are related to its antimitotic activities, wherein apoptosis of cancer cells is induced following prolonged and irreversible mitotic blockade.[19][20] In addition to its cytotoxic, antimitotic-based mechanisms, preclinical studies in human breast cancer models have shown that eribulin also exerts complex effects on the biology of surviving cancer cells and residual tumors that appear unrelated to its antimitotic effects. These non-mitotic mechanisms include vascular remodeling that leads to increased tumor perfusion and mitigation of tumor hypoxia, phenotypic changes consistent with reversal of epithelial-mesenchymal transition (EMT), and decreased capacity for migration and invasion leading to reduced metastatic capacity as measured in a preclinical experimental metastasis model.[21][22] In other studies, eribulin treatment of leiomyosarcoma and liposarcoma cells leads to increased expression of smooth muscle and adipocyte differentiation antigens, respectively.[23] Taxane-resistant cancers are often unresponsive to eribulin. A recent study found that this resistance is due to expression of multidrug resistance protein 1 (MDR1).[24] Fluorescently labeled eribulin has been used to study the pharmacokinetics and pharmacodynamics at single cell level in vivo.[24]

A new synthetic route to the drug was published in 2009.[25]

References

  1. ^ https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=001&Appl_No=201532&Appl_type=N[full citation needed]
  2. ^ "FDA approves new treatment option for late-stage breast cancer" (Press release). USFDA. 2010-11-15. Retrieved November 15, 2010.
  3. ^ Notice of Decision for HALAVEN[permanent dead link‍]
  4. ^ https://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/drugandbiologicapprovalreports/ndaandblaapprovalreports/ucm544019.pdf[full citation needed]
  5. ^ https://www.fda.gov/downloads/drugs/developmentapprovalprocess/smallbusinessassistance/ucm447307.pdf[full citation needed]
  6. ^ a b FDA approves first drug to show survival benefit in liposarcoma. Jan 2016
  7. ^ http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389[full citation needed]
  8. ^ https://clinicaltrials.gov/ct2/show/NCT03207672?cond=E7389+Liposomal&rank=1[full citation needed]
  9. ^ Yu, Yanke; Desjardins, Christopher; Saxton, Phil; Lai, George; Schuck, Edgar; Wong, Y. Nancy (2013). "Characterization of the pharmacokinetics of a liposomal formulation of eribulin mesylate (E7389) in mice". International Journal of Pharmaceutics. 443 (1–2): 9–16. doi:10.1016/j.ijpharm.2013.01.010. PMID 23313921.
  10. ^ https://clinicaltrials.gov/ct2/show/NCT03222856?term=eribulin+and+pembrolizumab&rank=1[full citation needed]
  11. ^ Towle, M. J; Salvato, K. A; Budrow, J; Wels, B. F; Kuznetsov, G; Aalfs, K. K; Welsh, S; Zheng, W; Seletsky, B. M; Palme, M. H; Habgood, G. J; Singer, L. A; Dipietro, L. V; Wang, Y; Chen, J. J; Quincy, D. A; Davis, A; Yoshimatsu, K; Kishi, Y; Yu, M. J; Littlefield, B. A (2001). "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B". Cancer Research. 61 (3): 1013–21. PMID 11221827.
  12. ^ Yu MJ, Kishi Y, Littlefield BA (2005). "Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B". In Newman DJ, Kingston DGI, Cragg, GM (ed.). Anticancer agents from natural products. Washington, DC: Taylor & Francis. ISBN 978-0-8493-1863-4.{{cite book}}: CS1 maint: multiple names: authors list (link)[page needed]
  13. ^ Hirata, Y; Uemura, D (1986). "Halichondrins - antitumor polyether macrolides from a marine sponge". Pure and Applied Chemistry. 58 (5): 701–710. doi:10.1351/pac198658050701.
  14. ^ Bai, R. L; Paull, K. D; Herald, C. L; Malspeis, L; Pettit, G. R; Hamel, E (1991). "Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data". The Journal of Biological Chemistry. 266 (24): 15882–9. PMID 1874739.
  15. ^ Jordan, M. A; Kamath, K; Manna, T; Okouneva, T; Miller, H. P; Davis, C; Littlefield, B. A; Wilson, L (2005). "The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth". Molecular Cancer Therapeutics. 4 (7): 1086–95. doi:10.1158/1535-7163.MCT-04-0345. PMID 16020666.
  16. ^ Okouneva, T; Azarenko, O; Wilson, L; Littlefield, B. A; Jordan, M. A (2008). "Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase". Molecular Cancer Therapeutics. 7 (7): 2003–11. doi:10.1158/1535-7163.MCT-08-0095. PMC 2562299. PMID 18645010.
  17. ^ Smith, Jennifer A; Wilson, Leslie; Azarenko, Olga; Zhu, Xiaojie; Lewis, Bryan M; Littlefield, Bruce A; Jordan, Mary Ann (2010). "Eribulin Binds at Microtubule Ends to a Single Site on Tubulin to Suppress Dynamic Instability". Biochemistry. 49 (6): 1331–7. doi:10.1021/bi901810u. PMC 2846717. PMID 20030375.
  18. ^ Wilson, Leslie; Lopus, Manu; Miller, Herbert P; Azarenko, Olga; Riffle, Stephen; Smith, Jennifer A; Jordan, Mary Ann (2015). "Effects of Eribulin on Microtubule Binding and Dynamic Instability Are Strengthened in the Absence of the βIII Tubulin Isotype". Biochemistry. 54 (42): 6482–9. doi:10.1021/acs.biochem.5b00745. PMID 26435331.
  19. ^ Kuznetsov, Galina; Towle, Murray J; Cheng, Hongsheng; Kawamura, Takanori; Tendyke, Karen; Liu, Diana; Kishi, Yoshito; Yu, Melvin J; Littlefield, Bruce A (2004). "Induction of Morphological and Biochemical Apoptosis following Prolonged Mitotic Blockage by Halichondrin B Macrocyclic Ketone Analog E7389". Cancer Research. 64 (16): 5760–6. doi:10.1158/0008-5472.CAN-04-1169. PMID 15313917.
  20. ^ Towle, M. J; Salvato, K. A; Wels, B. F; Aalfs, K. K; Zheng, W; Seletsky, B. M; Zhu, X; Lewis, B. M; Kishi, Y; Yu, M. J; Littlefield, B. A (2010). "Eribulin Induces Irreversible Mitotic Blockade: Implications of Cell-Based Pharmacodynamics for in vivo Efficacy under Intermittent Dosing Conditions". Cancer Research. 71 (2): 496–505. doi:10.1158/0008-5472.CAN-10-1874. PMID 21127197.
  21. ^ Funahashi, Yasuhiro; Okamoto, Kiyoshi; Adachi, Yusuke; Semba, Taro; Uesugi, Mai; Ozawa, Yoichi; Tohyama, Osamu; Uehara, Taisuke; Kimura, Takayuki; Watanabe, Hideki; Asano, Makoto; Kawano, Satoshi; Tizon, Xavier; McCracken, Paul J; Matsui, Junji; Aoshima, Ken; Nomoto, Kenichi; Oda, Yoshiya (2014). "Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models". Cancer Science. 105 (10): 1334–42. doi:10.1111/cas.12488. PMC 4462349. PMID 25060424.
  22. ^ Yoshida, T; Ozawa, Y; Kimura, T; Sato, Y; Kuznetsov, G; Xu, S; Uesugi, M; Agoulnik, S; Taylor, N; Funahashi, Y; Matsui, J (2014). "Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial–mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET) states". British Journal of Cancer. 110 (6): 1497–505. doi:10.1038/bjc.2014.80. PMC 3960630. PMID 24569463.
  23. ^ Kawano, S; Asano, M; Adachi, Y; Matsui, J (2016). "Antimitotic and Non-mitotic Effects of Eribulin Mesilate in Soft Tissue Sarcoma". Anticancer Research. 36 (4): 1553–61. PMID 27069131.
  24. ^ a b Laughney AM, Kim E, Sprachman MM, Miller MA, Kohler RH, Yang KS, Orth JD, Mitchison TJ, Weissleder R (2014). "Single-cell pharmacokinetic imaging reveals a therapeutic strategy to overcome drug resistance to the microtubule inhibitor eribulin". Science Translational Medicine. 6 (261): 261ra152. doi:10.1126/scitranslmed.3009318. PMC 4330962. PMID 25378644.
  25. ^ Kim, Dae-Shik; Dong, Cheng-Guo; Kim, Joseph T; Guo, Haibing; Huang, Jian; Tiseni, Paolo S; Kishi, Yoshito (2009). "New Syntheses of E7389 C14−C35 and Halichondrin C14−C38 Building Blocks: Double-Inversion Approach". Journal of the American Chemical Society. 131 (43): 15636–41. doi:10.1021/ja9058475. PMID 19807076.
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