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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 mass729.90 g/mol g·mol−1
3D model (JSmol)
  • O=C(C[C@@H]1[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]1C[C@H]2O[C@@H](CC[C@H]3C(C[C@H](CCC[C@@]4(C5)O6)O3)=C)C[C@@H](C)C2=C)C[C@@H]7O[C@@]([C@H]6[C@H](O[C@H]5[C@@H]8O4)[C@H]8O9)([H])[C@]9([H])CC7
  • 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.

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.[1] 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.[2]

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.[3] 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.[3]

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.[4]

Structure and mechanism

Eribulin is a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B,[5][6] the parent molecule being a potent naturally occurring mitotic inhibitor with a unique mechanism of action found in the Halichondria genus of sponges.[7][8]

Eribulin is a mechanistically unique inhibitor of microtubule dynamics,[9][10] binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.[11][12] 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.[13][14] 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.[15][16] In other studies, eribulin treatment of leiomyosarcoma and liposarcoma cells leads to increased expression of smooth muscle and adipocyte differentiation antigens, respectively.[17]

A new synthetic route to the drug was published in 2009.[18]

References

  1. ^ "FDA approves new treatment option for late-stage breast cancer" (Press release). USFDA. 2010-11-15. Retrieved November 15, 2010.
  2. ^ Notice of Decision for HALAVEN
  3. ^ a b FDA approves first drug to show survival benefit in liposarcoma. Jan 2016
  4. ^ http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389
  5. ^ Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (February 2001). "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B". Cancer Res. 61 (3): 1013–21. PMID 11221827.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ 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 0-8493-1863-7.{{cite book}}: CS1 maint: multiple names: authors list (link)
  7. ^ Hirata Y, Uemura D (1986). "Halichondrins - antitumor polyether macrolides from a marine sponge". Pure Appl. Chem. 58 (5): 701–710. doi:10.1351/pac198658050701.
  8. ^ Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E (August 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". J. Biol. Chem. 266 (24): 15882–9. PMID 1874739.
  9. ^ Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L (July 2005). "The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth". Mol. Cancer Ther. 4 (7): 1086–95. doi:10.1158/1535-7163.MCT-04-0345. PMID 16020666.
  10. ^ Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA (July 2008). "Inhibition of Centromere Dynamics by Eribulin (E7389) during Mitotic Metaphase". Mol. Cancer Ther. 7 (7): 2003–11. doi:10.1158/1535-7163.MCT-08-0095. PMC 2562299. PMID 18645010.
  11. ^ Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA (February 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.
  12. ^ Wilson, L; Lopus, M; Miller, HP; Azarenko, O; Riffle, S; Smith, JA; Jordan, MA (2015). "Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the βIII tubulin isotype". Biochemistry. 54: 6482–9. doi:10.1021/acs.biochem.5b00745. PMID 26435331.
  13. ^ Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA (August 2004). "Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389". Cancer Res. 64 (16): 5760–6. doi:10.1158/0008-5472.CAN-04-1169. PMID 15313917.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis BM, Kishi Y, Yu MJ, Littlefield BA (January 2011). "Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions". Cancer Res. 71 (2): 496–505. doi:10.1158/0008-5472.CAN-10-1874. PMID 21127197.
  15. ^ Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, Tohyama O, Uehara T, Kimura T, Watanabe H, Asano M, Kawano S, Tizon X, McCracken PJ, Matsui J, Aoshima K, Nomoto K, Oda Y (October 2014). "Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models". Cancer Sci. 105 (10): 1334–42. doi:10.1111/cas.12488. PMID 25060424.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, Uesugi M, Agoulnik S, Taylor N, Funahashi Y, Matsui J (March 2014). "Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states". Br. J. Cancer. 110 (6): 1497–505. doi:10.1038/bjc.2014.80. PMID 24569463.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Kawano S, Asano M, Adachi Y, Matsui J (April 2016). "Antimitotic and non-mitotic effects of eribulin mesilate in soft tissue sarcoma". Anticancer Res. 36 (4): 1553–61. PMID 27069131.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Kim DS, Dong CG, Kim JT, Guo H, Huang J, Tiseni PS, Kishi Y (November 2009). "New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach". J. Am. Chem. Soc. 131 (43): 15636–41. doi:10.1021/ja9058475. PMID 19807076.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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