Chemistry:Eribulin

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Eribulin, sold under the brand name Halaven among others, is an intravenously administered anti-cancer medication used to treat certain patients with breast cancer and liposarcoma.[1][2] Eribulin was approved for medical use in the United States in November 2010,[3] the European Union in March 2011,[2] Japan in April 2011,[4] and Canada in December 2011.[5][6][7] It is available in some jurisdictions as a generic medication.[8]

Medical uses

Eribulin is indicated for the treatment of certain patients with locally advanced or metastatic breast cancer,[2][9][10][11][12][4] and for the treatment of adults with unresectable liposarcoma.[2][13][14] Details of the specific patient populations covered for use can be found in the various country- or region-specific regulatory approval documention.

Adverse effects

The most serious potential side effects of eribulin include severe neutropenia, peripheral neuropathy, effects on heartbeat (QT prolongation) and harm to developing fetuses.[3] Other common side effects can include anaemia, fatigue, nausea, hair loss (alopecia), constipation, decreased levels of potassium or calcium, abdominal pain, and pyrexia (fever).[3][13]

Structure and mechanism

Eribulin (previously, B1939, ER-086526, E7389, NSC-707389) is a fully synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B,[15][16] a naturally occurring, potent mitotic inhibitor with a unique tubulin-based mechanism of action.[17] Eribulin's parent molecule, halichondrin B, was originally found in the marine sponge Halichondria okadai.[18][17]

At the molecular level, eribulin is a mechanistically unique inhibitor of microtubule dynamics,[19][20] binding to a small number of high affinity sites at open plus ends of growing microtubules.[21][22] Eribulin's near-exclusive preference for microtubule plus end binding (versus microtubule side or minus end binding) results from its ability to distinguish between GTP-β-tubulin present at growing microtubule plus ends versus the GDP-β-tubulin which characterizes mature microtubule sides below the active polymerization sites at microtubule plus ends.[23] The basis for eribulin's ability to discriminate between GTP-β-tubulin and GDP-β-tubulin is direct physical contact between eribulin's so-called "cage structure" at C8-C14 and the ribose moiety of the β-tubulin-embedded guanosine nucleotide.[24]

Therapeutically, eribulin has both cytotoxic and non-cytotoxic mechanisms of action. Its cytotoxic effects are related to its tubulin-based antimitotic activities, wherein apoptosis of cancer cells is induced following prolonged and irreversible mitotic blockade.[25][26] Eribulin-induced apoptosis is characterized by immunogenic cell death.[27] In addition to its cytotoxic mechanisms, eribulin also exerts complex non-cytotoxic effects on the biology of residual cancer cells, the tumor microenvironment and tumor-host immune responses. Such non-cytotoxic effects appear unrelated to its antimitotic mechanisms, but rather to inhibited interphase microtubule dynamics with consequent effects on plus end binding proteins (+TIPS) and assembly of related signaling scaffolds.[28][29] Eribulin's non-cytotoxic mechanisms include (i) vascular remodeling that leads to increased tumor perfusion and mitigation of tumor hypoxia, (ii) phenotypic changes in residual cancer cells consistent with reversal of epithelial-mesenchymal transition (EMT), (iii) decreased capacity for migration and invasion leading to reduced metastatic capacity, and (iv) stimulation of and synergy with the cGAS-STING innate immune signaling pathway.[30][31][32][33] Other studies showed that eribulin treatment of leiomyosarcoma and liposarcoma cells leads to increased expression of smooth muscle and adipocyte differentiation antigens, respectively,[34] supporting eribulin's ability to alter cancer cell phenotypes regardless of epithelial versus mesenchymal cell type of origin. Recent studies have shown that eribulin's effects on tumor vasculature involve phenotypic maturation of vascular pericytes, resulting in normalization of the tumor vascular bed.[35] Eribulin's phenotypic effects on both tumor cells and tumor-associated stroma have been linked to chromatin remodeling driven by epigenetic changes in DNA methylation patterns and DNA methyltransferase activities.[36][37]

Taxane-resistant cancers are often unresponsive to eribulin, although paradoxically eribulin's regulatory approvals in breast cancer were based on increased overall survival (OS) in patients who had previously progressed on taxanes.[3][4][38] A 2014 study found that post-taxane eribulin resistance is due to expression of the P-glycoprotein (PgP) multidrug resistance protein 1 (MDR1).[39] Eribulin had previously been shown to be a PgP substrate with the ability to inhibit PgP-mediated drug efflux in cell-based efflux models.[40] Fluorescently labeled eribulin has been used to study the pharmacokinetics and pharmacodynamics at single cell level in vivo.[39]

Eribulin's chemical structure (as ER-086526) was originally published in 2001,[15] and its synthesis was first published in 2004.[41]

Discovery

Eribulin's natural product parent, halichondrin B (HB), was first reported by Hirata and Uemura in 1986, in a paper that demonstrated HB's exquisite anticancer potency against murine cancer cells in vitro and tumor models in vivo.[18] Shortly thereafter, Professor Yoshito Kishi of the Department of Chemistry at Harvard University and his team undertook HB's total synthesis, which they first reported in 1992.[42] Earlier, Kishi had established collaborations with Eisai Research Institute (ERI) in Andover, Massachusetts to evaluate the biological activities of his fully synthetic HB as well as its synthetic intermediates. In July, 1992 ERI scientists confirmed the biological activity of Kishi's synthetic HB at potencies comparable to those reported for the naturally-occurring compound by Hirata and Uemura in 1986.[18] A month later using Kishi's synthetic intermediates, ERI scientists discovered that HB's anticancer activity resides in its so-called Right Half (RH; C1-C38) moiety, which incorporates the macrocyclic lactone and represents about 2/3 of the full HB molecule[16] (see also footnote 3 of Towle et al., 2001[15]). The discovery that HB's anticancer activity resided in RH suggested the possibility that smaller, structurally less complex compounds could be used as starting points for anticancer drug development. Over the next 6 years, more than 200 RH analogs, consisting first of macrocyclic lactones followed by macrocyclic ketones, were synthesized at both ERI and Harvard, with biological evaluations done at ERI. In 1998, macrocyclic ketone ER-086526[15] (later known as E7389 then eribulin) was synthesized by ERI chemists, a milestone commemorated by the spelling of its eventual International Nonproprietary Name (INN)-approved generic name, ERIbulin. Eribulin's potent in vitro and in vivo anticancer activity, first shown by ERI scientists,[15] was subsequently confirmed by the U.S. National Cancer Institute (NCI)[43] working under a Cooperative Research and Development Agreement (CRADA) created with ERI to support preclinical IND-enabling studies. In 2002, NCI sponsored the first-in-human Phase I clinical trial of eribulin using compound supplied by ERI. This trial, conducted by the California Cancer Consortium and led by City of Hope Comprehensive Cancer Center in Duarte, California,[44][45] established the still-current dosing schedule of 1.4 mg/m2 on days 1 and 8 of a 21-day cycle.[3] Development-path Phase II and Phase III clinical trials were subsequently sponsored by Eisai.

Research

Eribulin is being investigated for use in a variety of cancer types as monotherapy or in combination with other agents. As of April, 2026, currently recruiting studies include various breast cancer subtypes, ovarian and uterine carcinosarcomas, melanoma, liposarcoma, leiomyosarcoma, various other sarcomas and pediatric solid tumors, and various other advanced solid tumor types.[46]

Two 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 in Phase I clinical trials.[47] Preliminary in vivo experiments show a decrease in C(max) and a longer half-life with the liposomal formulation.[48] 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.[49]

References

  1. ↑ "Halaven- eribulin mesylate injection". 22 December 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=31ce4750-ded5-4a0b-95e9-f229fa6bc822. 
  2. ↑ 2.0 2.1 2.2 2.3 Cite error: Invalid <ref> tag; no text was provided for refs named Halaven EPAR
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Drug Approval Package: Halaven (erbulin mesylate) NDA 201532". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201532s000_halaven_TOC.cfm. 
  4. ↑ 4.0 4.1 4.2 "HALAVEN® RECEIVES APPROVAL IN JAPAN FOR THE TREATMENT OF INOPERABLE AND RECURRENT BREAST CANCER | News Release：2011 | Eisai Co., Ltd.". https://www.eisai.com/news/news201133.html. 
  5. ↑ "Halaven Product information". 22 October 2009. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=86314. 
  6. ↑ "Halaven for Metastatic Breast Cancer". 9 March 2015. https://www.cadth.ca/halaven-metastatic-breast-cancer-details. 
  7. ↑ "Eisai Announces Canadian Approval of its Anticancer Agent Halaven". Eisai Co., Ltd. (Press release). Retrieved 9 July 2020.
  8. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Mevlyq EPAR
  9. ↑ "FDA approves new treatment option for late-stage breast cancer" (Press release). U.S. Food and Drug Administration (FDA). 15 November 2010. Archived from the original on 17 November 2010. Retrieved 15 November 2010.
  10. ↑ "Eribulin". 28 January 2016. https://www.fda.gov/drugs/resources-information-approved-drugs/eribulin. 
  11. ↑ "Halaven for Metastatic Breast Cancer". 9 March 2015. https://www.cadth.ca/halaven-metastatic-breast-cancer-details. 
  12. ↑ "Eisai Announces Canadian Approval of its Anticancer Agent Halaven". Eisai Co., Ltd. (Press release). Retrieved 9 July 2020.
  13. ↑ 13.0 13.1 "FDA approves first drug to show survival benefit in liposarcoma". U.S. Food and Drug Administration (FDA) (Press release). 28 January 2016. Retrieved 9 July 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  14. ↑ "U.S. FDA Approves Eisai's Anticancer Agent Halaven For The Treatment Of Advanced Liposarcoma" (Press release). Eisai Co., Ltd. 29 January 2016. Retrieved 15 February 2021.
  15. ↑ 15.0 15.1 15.2 15.3 15.4 "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B". Cancer Research 61 (3): 1013–1021. February 2001. PMID 11221827. 
  16. ↑ 16.0 16.1 "Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B". Anticancer agents from natural products (2nd ed.). Boca Raton, FL: CRC Press. 2012. pp. 317–345. ISBN 978-1-4398-1382-9. 
  17. ↑ 17.0 17.1 "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): 15882–15889. August 1991. doi:10.1016/S0021-9258(18)98491-7. PMID 1874739. 
  18. ↑ 18.0 18.1 18.2 "Halichondrins - antitumor polyether macrolides from a marine sponge". Pure and Applied Chemistry 58 (5): 701–710. 1 January 1986. doi:10.1351/pac198658050701. ISSN 1365-3075. Bibcode: 1986PApCh..58..701H. 
  19. ↑ "The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth". Molecular Cancer Therapeutics 4 (7): 1086–1095. July 2005. doi:10.1158/1535-7163.MCT-04-0345. PMID 16020666. 
  20. ↑ "Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase". Molecular Cancer Therapeutics 7 (7): 2003–2011. July 2008. doi:10.1158/1535-7163.MCT-08-0095. PMID 18645010. 
  21. ↑ "Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability". Biochemistry 49 (6): 1331–1337. February 2010. doi:10.1021/bi901810u. PMID 20030375. 
  22. ↑ "Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the βIII tubulin isotype". Biochemistry 54 (42): 6482–6489. October 2015. doi:10.1021/acs.biochem.5b00745. PMID 26435331. 
  23. ↑ "Eribulin's exclusive binding to microtubule plus ends results from discrimination between GTP and GDP forms of β-tubulin". Archives of Biochemistry and Biophysics 771. September 2025. doi:10.1016/j.abb.2025.110482. PMID 40449645. 
  24. ↑ "Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes". Current Biology 26 (13): 1713–1721. July 2016. doi:10.1016/j.cub.2016.04.053. PMID 27321995. Bibcode: 2016CBio...26.1713D. 
  25. ↑ "Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389". Cancer Research 64 (16): 5760–5766. August 2004. doi:10.1158/0008-5472.CAN-04-1169. PMID 15313917. 
  26. ↑ "Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions". Cancer Research 71 (2): 496–505. January 2011. doi:10.1158/0008-5472.CAN-10-1874. PMID 21127197. 
  27. ↑ "Eribulin Induction of Immunogenic Cell Death (ICD): Comparison With Other Cytotoxic Agents and Temporal Relationship of ICD Biomarkers". Anticancer Research 45 (1): 39–53. January 2025. doi:10.21873/anticanres.17391. PMID 39740820. 
  28. ↑ "Eribulin disrupts EB1-microtubule plus-tip complex formation". Cell Cycle 13 (20): 3218–3221. 2014. doi:10.4161/15384101.2014.950143. PMID 25485501. 
  29. ↑ "Regulation of E-cadherin localization by microtubule targeting agents: rapid promotion of cortical E-cadherin through p130Cas/Src inhibition by eribulin". Oncotarget 9 (5): 5545–5561. January 2018. doi:10.18632/oncotarget.23798. PMID 29464017. 
  30. ↑ "Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models". Cancer Science 105 (10): 1334–1342. October 2014. doi:10.1111/cas.12488. PMID 25060424. 
  31. ↑ "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): 1497–1505. March 2014. doi:10.1038/bjc.2014.80. PMID 24569463. 
  32. ↑ "Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA". Molecular Pharmacology 100 (4): 309–318. October 2021. doi:10.1124/molpharm.121.000297. PMID 34312217. 
  33. ↑ "The Microtubule Destabilizer Eribulin Synergizes with STING Agonists to Promote Antitumor Efficacy in Triple-Negative Breast Cancer Models". Cancers 14 (23): 5962. December 2022. doi:10.3390/cancers14235962. PMID 36497445. 
  34. ↑ "Antimitotic and Non-mitotic Effects of Eribulin Mesilate in Soft Tissue Sarcoma". Anticancer Research 36 (4): 1553–1561. April 2016. PMID 27069131. 
  35. ↑ "Selective tubulin-binding drugs induce pericyte phenotype switching and anti-cancer immunity". EMBO Molecular Medicine 17 (5): 1071–1100. May 2025. doi:10.1038/s44321-025-00222-6. PMID 40140727. 
  36. ↑ "Pharmacological induction of chromatin remodeling drives chemosensitization in triple-negative breast cancer". Cell Reports. Medicine 5 (4). April 2024. doi:10.1016/j.xcrm.2024.101504. PMID 38593809. 
  37. ↑ "Alteration of DNA methyltransferases by eribulin elicits broad DNA methylation changes with potential therapeutic implications for triple-negative breast cancer". Epigenomics 16 (5): 293–308. March 2024. doi:10.2217/epi-2023-0339. PMID 38356412. 
  38. ↑ "Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study". Lancet 377 (9769): 914–923. March 2011. doi:10.1016/S0140-6736(11)60070-6. PMID 21376385. https://pubmed.ncbi.nlm.nih.gov/21376385. 
  39. ↑ 39.0 39.1 "Single-cell pharmacokinetic imaging reveals a therapeutic strategy to overcome drug resistance to the microtubule inhibitor eribulin". Science Translational Medicine 6 (261): 261ra152. November 2014. doi:10.1126/scitranslmed.3009318. PMID 25378644. 
  40. ↑ "Interactions between the chemotherapeutic agent eribulin mesylate (E7389) and P-glycoprotein in CF-1 abcb1a-deficient mice and Caco-2 cells". Xenobiotica; The Fate of Foreign Compounds in Biological Systems 41 (4): 320–326. April 2011. doi:10.3109/00498254.2010.542256. PMID 21162698. 
  41. ↑ "Macrocyclic ketone analogues of halichondrin B". Bioorganic & Medicinal Chemistry Letters 14 (22): 5551–5554. November 2004. doi:10.1016/j.bmcl.2004.08.069. PMID 15482922. 
  42. ↑ "Total synthesis of halichondrin B and norhalichondrin B". Journal of the American Chemical Society 114 (8): 3162–3164. April 1992. doi:10.1021/ja00034a086. ISSN 0002-7863. 
  43. ↑ "Comparison of the activities of the truncated halichondrin B analog NSC 707389 (E7389) with those of the parent compound and a proposed binding site on tubulin". Molecular Pharmacology 70 (6): 1866–1875. December 2006. doi:10.1124/mol.106.026641. PMID 16940412. 
  44. ↑ "A phase I pharmacokinetic and target validation study of the novel anti-tubulin agent E7389: A California Cancer Consortium trial". Journal of Clinical Oncology 23 (16_suppl): 3036–3036. June 2005. doi:10.1200/jco.2005.23.16_suppl.3036. ISSN 0732-183X. 
  45. ↑ "Pharmacodynamics (PD) and pharmacokinetics (PK) of E7389 (eribulin, halichondrin B analog) during a phase I trial in patients with advanced solid tumors: a California Cancer Consortium trial". Cancer Chemotherapy and Pharmacology 76 (5): 897–907. November 2015. doi:10.1007/s00280-015-2868-7. PMID 26362045. PMC 4694049. https://pubmed.ncbi.nlm.nih.gov/26362045. 
  46. ↑ "64 studies currently listed as recruiting or not yet recruiting for eribulin or E7389 as of 4-28-2026. Does not include completed studies.". clinicaltrials.gov. U.S. National Library of Medicine. http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389. 
  47. ↑ Clinical trial number NCT03207672 for "Study of E7389 Liposomal Formulation in Subjects With Solid Tumor" at ClinicalTrials.gov
  48. ↑ "Characterization of the pharmacokinetics of a liposomal formulation of eribulin mesylate (E7389) in mice". International Journal of Pharmaceutics 443 (1–2): 9–16. February 2013. doi:10.1016/j.ijpharm.2013.01.010. PMID 23313921. 
  49. ↑ Clinical trial number NCT03222856 for "Ph II Study of Pembrolizumab & Eribulin in Patients With HR+/HER2- MBC Previously Treated With Anthracyclines & Taxanes (KELLY)" at ClinicalTrials.gov



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