Eribulin

{{Short description|Pharmaceutical drug}} {{Use dmy dates|date=February 2024}} {{cs1 config |name-list-style=vanc|display-authors=6}} {{Infobox drug | Verifiedfields = changed | verifiedrevid = 461094948 | image = Eribulin.svg | image_class = skin-invert-image | width = 300 | alt = | caption = | USAN = eribulin mesylate | JAN = eribulin mesilate

| pronounce = | tradename = Halaven, Mevlyq | Drugs.com = {{drugs.com|monograph|eribulin-mesylate}} | MedlinePlus = a611007 | DailyMedID = Eribulin | pregnancy_AU = D | pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Eribulin (Halaven) Use During Pregnancy | website=Drugs.com | date=22 October 2019 | url=https://www.drugs.com/pregnancy/eribulin.html | access-date=9 July 2020}}</ref> | pregnancy_category = | routes_of_administration = Intravenous | class = Antineoplastic | ATC_prefix = L01 | ATC_suffix = XX41 | ATC_supplemental =  | legal_AU = S4 | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref name="CA Halaven PI" /> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = <ref>{{cite web | title=Halaven 0.44 mg/ml solution for injection | website=(emc) | date=16 January 2023 | url=https://www.medicines.org.uk/emc/product/4517/smpc | access-date=16 December 2023}}</ref> | legal_US = Rx-only | legal_US_comment = <ref name="Halaven FDA label" /> | legal_EU = Rx-only | legal_EU_comment = <ref name="Halaven EPAR">{{cite web | title=Halaven EPAR | website=European Medicines Agency (EMA) | date=17 March 2011 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/halaven | access-date=16 December 2023}}</ref><ref name="Mevlyq EPAR">{{cite web | title=Mevlyq EPAR | website=European Medicines Agency (EMA) | date=9 February 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/mevlyq | access-date=19 February 2024}}</ref><ref>{{cite web | title=Mevlyq product information | website=Union Register of medicinal products | date=13 February 2024 | url=https://ec.europa.eu/health/documents/community-register/html/h1789.htm | access-date=19 February 2024}}</ref> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only<ref>{{cite press release | title=Eisai Announces Japan Launch Of Anticancer Agent Halaven | publisher=Eisai Co., Ltd. | date=19 July 2011 | url=https://www.eisai.com/news/news201155.html | access-date=15 February 2021}}</ref><ref>{{cite press release | title=Anticancer Agent Halaven Approved For Treatment Of Locally Advanced Or Metastatic Breast Cancer In China | publisher=Eisai Co., Ltd. | date=17 July 2019 | url=https://www.eisai.com/news/2019/news201952.html | access-date=15 February 2021}}</ref>

| bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion =  | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 253128-41-5 | CAS_supplemental = | PubChem = 11354606 | IUPHAR_ligand = | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB08871 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 24721813 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = LR24G6354G | KEGG_Ref = | KEGG = D08914 | ChEBI_Ref = | ChEBI = 63587 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1683590 | NIAID_ChemDB = | PDB_ligand = | synonyms = B1939, ER-086526, E7389, NSC-707389

| IUPAC_name = 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-9''H'',15''H''-furo(3,2-i)furo(2',3'-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4''H'')-one | C = 40 | H = 59 | N = 1 | O = 11 | SMILES = CC1CC2CCC3C(=C)CC(O3)CCC45CC6C(O4)C7C(O6)C(O5)C8C(O7)CCC(O8)CC(=O)CC9C(CC(C1=C)O2)OC(C9OC)CC(CN)O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C40H59NO11/c1-19-11-24-5-7-28-20(2)12-26(45-28)9-10-40-17-33-36(51-40)37-38(50-33)39(52-40)35-29(49-37)8-6-25(47-35)13-22(42)14-27-31(16-30(46-24)21(19)3)48-32(34(27)44-4)15-23(43)18-41/h19,23-39,43H,2-3,5-18,41H2,1,4H3/t19-,23+,24+,25-,26+,27+,28+,29+,30-,31+,32-,33-,34-,35+,36+,37+,38-,39+,40+/m1/s1 | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = UFNVPOGXISZXJD-JBQZKEIOSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''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.<ref name="Halaven FDA label">{{cite web | title=Halaven- eribulin mesylate injection | website=DailyMed | date=22 December 2017 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=31ce4750-ded5-4a0b-95e9-f229fa6bc822 | access-date=9 July 2020}}</ref><ref name="Halaven EPAR" /> Eribulin was approved for medical use in the United States in November 2010,<ref name=":0">{{cite web | title=Drug Approval Package: Halaven (erbulin mesylate) NDA 201532 | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201532s000_halaven_TOC.cfm | access-date=9 July 2020}}</ref> the European Union in March 2011,<ref name="Halaven EPAR" /> Japan in April 2011,<ref name=":1">{{Cite web |title=HALAVEN® RECEIVES APPROVAL IN JAPAN FOR THE TREATMENT OF INOPERABLE AND RECURRENT BREAST CANCER {{!}} News Release：2011 {{!}} Eisai Co., Ltd. |url=https://www.eisai.com/news/news201133.html |access-date=2026-04-19 |website=www.eisai.com}}</ref> and Canada in December 2011.<ref name="CA Halaven PI">{{cite web | title=Halaven Product information | website=Health Canada | date=22 October 2009 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=86314 | access-date=16 December 2023}}</ref><ref>{{cite web | title=Halaven for Metastatic Breast Cancer | website=Canadian Agency for Drugs and Technologies in Health | date=9 March 2015 | url=https://www.cadth.ca/halaven-metastatic-breast-cancer-details | access-date=9 July 2020 | archive-date=9 July 2020 | archive-url=https://web.archive.org/web/20200709223650/https://www.cadth.ca/halaven-metastatic-breast-cancer-details }}</ref><ref>{{cite press release | title=Eisai Announces Canadian Approval of its Anticancer Agent Halaven | website=Eisai Co., Ltd. | url=https://www.eisai.com/news/news201179.html | access-date=9 July 2020}}</ref> It is available in some jurisdictions as a generic medication.<ref name="Mevlyq EPAR" />

== Medical uses == Eribulin is indicated for the treatment of certain patients with locally advanced or metastatic breast cancer,<ref name="Halaven EPAR" /><ref>{{cite press release | title = FDA approves new treatment option for late-stage breast cancer | publisher = U.S. Food and Drug Administration (FDA) | date = 15 November 2010 | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm233863.htm | access-date = 15 November 2010 | archive-url = https://web.archive.org/web/20101117013510/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm233863.htm | archive-date = 17 November 2010 }}</ref><ref>{{cite web | title=Eribulin | website=U.S. Food and Drug Administration | date=28 January 2016 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/eribulin | access-date=16 December 2023}}</ref><ref>{{cite web | title=Halaven for Metastatic Breast Cancer | website=Canadian Agency for Drugs and Technologies in Health | date=9 March 2015 | url=https://www.cadth.ca/halaven-metastatic-breast-cancer-details | access-date=9 July 2020 | archive-date=9 July 2020 | archive-url=https://web.archive.org/web/20200709223650/https://www.cadth.ca/halaven-metastatic-breast-cancer-details }}</ref><ref>{{cite press release | title=Eisai Announces Canadian Approval of its Anticancer Agent Halaven | website=Eisai Co., Ltd. | url=https://www.eisai.com/news/news201179.html | access-date=9 July 2020}}</ref><ref name=":1" /> and for the treatment of adults with unresectable liposarcoma.<ref name="Halaven EPAR" /><ref name="FDA-lipo2016">{{cite press release | title=FDA approves first drug to show survival benefit in liposarcoma | website=U.S. Food and Drug Administration (FDA) | date=28 January 2016 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-show-survival-benefit-liposarcoma | access-date=9 July 2020}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}} {{PD-notice}}</ref><ref>{{cite press release | title=U.S. FDA Approves Eisai's Anticancer Agent Halaven For The Treatment Of Advanced Liposarcoma | publisher=Eisai Co., Ltd. | date=29 January 2016 | url=https://www.eisai.com/news/news201604.html | access-date=15 February 2021}}</ref> 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.<ref name=":0" /> Other common side effects can include anaemia, fatigue, nausea, hair loss (alopecia), constipation, decreased levels of potassium or calcium, abdominal pain, and pyrexia (fever).<ref name=":0" /><ref name="FDA-lipo2016" />

==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,<ref name="pmid11221827">{{cite journal |vauthors=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 |date=February 2001 |title=In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B |journal=Cancer Research |volume=61 |issue=3 |pages=1013–1021 |pmid=11221827}}</ref><ref name="isbn0-8493-1863-7">{{cite book | vauthors = Yu MJ, Kishi Y, Littlefield BA | year = 2012 | veditors = Cragg GM, Kingston DG, Newman DJ | chapter = Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B | title = Anticancer agents from natural products | publisher = CRC Press | edition = 2nd | pages = 317–345 | isbn = 978-1-4398-1382-9 | author-link2 = Yoshito Kishi | location = Boca Raton, FL }}{{page needed|date=November 2017}}</ref> a naturally occurring, potent mitotic inhibitor with a unique tubulin-based mechanism of action.<ref name="pmid1874739" /> Eribulin's parent molecule, halichondrin B, was originally found in the marine sponge ''Halichondria okadai''.<ref name="Hirata_1986">{{cite journal |vauthors=Hirata Y, Uemura D |date=1 January 1986 |title=Halichondrins - antitumor polyether macrolides from a marine sponge |journal=Pure and Applied Chemistry |volume=58 |issue=5 |pages=701–710 |bibcode=1986PApCh..58..701H |doi=10.1351/pac198658050701 |issn=1365-3075 |s2cid=38138047 |doi-access=free |title-link=doi}}</ref><ref name="pmid1874739">{{cite journal |vauthors=Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E |date=August 1991 |title=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 |journal=The Journal of Biological Chemistry |volume=266 |issue=24 |pages=15882–15889 |doi=10.1016/S0021-9258(18)98491-7 |pmid=1874739 |doi-access=free |title-link=doi}}</ref>

At the molecular level, eribulin is a mechanistically unique inhibitor of microtubule dynamics,<ref name="pmid16020666">{{cite journal |vauthors=Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L |date=July 2005 |title=The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth |journal=Molecular Cancer Therapeutics |volume=4 |issue=7 |pages=1086–1095 |doi=10.1158/1535-7163.MCT-04-0345 |pmid=16020666 |s2cid=38459382 |doi-access=free |title-link=doi}}</ref><ref name="pmid18645010">{{cite journal |vauthors=Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA |date=July 2008 |title=Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase |journal=Molecular Cancer Therapeutics |volume=7 |issue=7 |pages=2003–2011 |doi=10.1158/1535-7163.MCT-08-0095 |pmc=2562299 |pmid=18645010}}</ref> binding to a small number of high affinity sites at open plus ends of growing microtubules.<ref name="pmid20030375">{{cite journal |vauthors=Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA |date=February 2010 |title=Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability |journal=Biochemistry |volume=49 |issue=6 |pages=1331–1337 |doi=10.1021/bi901810u |pmc=2846717 |pmid=20030375}}</ref><ref>{{cite journal |vauthors=Wilson L, Lopus M, Miller HP, Azarenko O, Riffle S, Smith JA, Jordan MA |date=October 2015 |title=Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the βIII tubulin isotype |journal=Biochemistry |volume=54 |issue=42 |pages=6482–6489 |doi=10.1021/acs.biochem.5b00745 |pmid=26435331}}</ref> 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.<ref>{{cite journal |vauthors=Agarwala KL, Kubara K, Seletsky BM, Sagane K, Littlefield BA |date=September 2025 |title=Eribulin's exclusive binding to microtubule plus ends results from discrimination between GTP and GDP forms of β-tubulin |journal=Archives of Biochemistry and Biophysics |volume=771 |article-number=110482 |doi=10.1016/j.abb.2025.110482 |pmid=40449645|doi-access=free }}</ref> 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.<ref>{{cite journal | vauthors = Doodhi H, Prota AE, Rodríguez-García R, Xiao H, Custar DW, Bargsten K, Katrukha EA, Hilbert M, Hua S, Jiang K, Grigoriev I, Yang CH, Cox D, Horwitz SB, Kapitein LC, Akhmanova A, Steinmetz MO | title = Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes | journal = Current Biology | volume = 26 | issue = 13 | pages = 1713–1721 | date = July 2016 | pmid = 27321995 | doi = 10.1016/j.cub.2016.04.053 | bibcode = 2016CBio...26.1713D }}</ref>

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.<ref name="pmid15313917">{{cite journal |vauthors=Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA |date=August 2004 |title=Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389 |journal=Cancer Research |volume=64 |issue=16 |pages=5760–5766 |doi=10.1158/0008-5472.CAN-04-1169 |pmid=15313917 |s2cid=30919443 |doi-access=free |title-link=doi}}</ref><ref name="pmid21127197">{{cite journal |vauthors=Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis BM, Kishi Y, Yu MJ, Littlefield BA |date=January 2011 |title=Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions |journal=Cancer Research |volume=71 |issue=2 |pages=496–505 |doi=10.1158/0008-5472.CAN-10-1874 |pmid=21127197 |doi-access=free |title-link=doi}}</ref> Eribulin-induced apoptosis is characterized by immunogenic cell death.<ref>{{cite journal |vauthors=Zang M, Zheng J, An X, Li BO, Yang H, Erickson B, Kunz R, Littlefield BA |date=January 2025 |title=Eribulin Induction of Immunogenic Cell Death (ICD): Comparison With Other Cytotoxic Agents and Temporal Relationship of ICD Biomarkers |journal=Anticancer Research |volume=45 |issue=1 |pages=39–53 |doi=10.21873/anticanres.17391 |pmid=39740820|doi-access=free }}</ref> 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.<ref>{{cite journal | vauthors = O'Rourke B, Yang CP, Sharp D, Horwitz SB | title = Eribulin disrupts EB1-microtubule plus-tip complex formation | journal = Cell Cycle | volume = 13 | issue = 20 | pages = 3218–3221 | date = 2014 | pmid = 25485501 | doi = 10.4161/15384101.2014.950143 | pmc = 4614316 }}</ref><ref>{{cite journal | vauthors = Dybdal-Hargreaves NF, Risinger AL, Mooberry SL | title = Regulation of E-cadherin localization by microtubule targeting agents: rapid promotion of cortical E-cadherin through p130Cas/Src inhibition by eribulin | journal = Oncotarget | volume = 9 | issue = 5 | pages = 5545–5561 | date = January 2018 | pmid = 29464017 | doi = 10.18632/oncotarget.23798 | pmc = 5814157 }}</ref> 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.<ref name="pmid25060424">{{cite journal |vauthors=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 |date=October 2014 |title=Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models |journal=Cancer Science |volume=105 |issue=10 |pages=1334–1342 |doi=10.1111/cas.12488 |pmc=4462349 |pmid=25060424}}</ref><ref name="pmid24569463">{{cite journal |vauthors=Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, Uesugi M, Agoulnik S, Taylor N, Funahashi Y, Matsui J |date=March 2014 |title=Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states |journal=British Journal of Cancer |volume=110 |issue=6 |pages=1497–1505 |doi=10.1038/bjc.2014.80 |pmc=3960630 |pmid=24569463}}</ref><ref>{{cite journal |vauthors=Fermaintt CS, Takahashi-Ruiz L, Liang H, Mooberry SL, Risinger AL |date=October 2021 |title=Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA |journal=Molecular Pharmacology |volume=100 |issue=4 |pages=309–318 |doi=10.1124/molpharm.121.000297 |pmc=8626644 |pmid=34312217}}</ref><ref>{{cite journal | vauthors = Takahashi-Ruiz L, Fermaintt CS, Wilkinson NJ, Chan PY, Mooberry SL, Risinger AL | date = December 2022 | title = The Microtubule Destabilizer Eribulin Synergizes with STING Agonists to Promote Antitumor Efficacy in Triple-Negative Breast Cancer Models | journal = Cancers | volume = 14 | issue = 23 | page = 5962 | doi = 10.3390/cancers14235962 | doi-access = free | pmc = 9740651 | pmid = 36497445 }}</ref> Other studies showed that eribulin treatment of leiomyosarcoma and liposarcoma cells leads to increased expression of smooth muscle and adipocyte differentiation antigens, respectively,<ref name="pmid27069131">{{cite journal |vauthors=Kawano S, Asano M, Adachi Y, Matsui J |date=April 2016 |title=Antimitotic and Non-mitotic Effects of Eribulin Mesilate in Soft Tissue Sarcoma |journal=Anticancer Research |volume=36 |issue=4 |pages=1553–1561 |pmid=27069131}}</ref> 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.<ref>{{cite journal |vauthors=He B, Wood KH, Li ZJ, Ermer JA, Li J, Bastow ER, Sakaram S, Darcy PK, Spalding LJ, Redfern CT, Canes J, Oliveira M, Prat A, Cortes J, Thompson EW, Littlefield BA, Redfern A, Ganss R |date=May 2025 |title=Selective tubulin-binding drugs induce pericyte phenotype switching and anti-cancer immunity |journal=EMBO Molecular Medicine |volume=17 |issue=5 |pages=1071–1100 |doi=10.1038/s44321-025-00222-6 |pmc=12081767 |pmid=40140727}}</ref> 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.<ref>{{cite journal |vauthors=Bagheri M, Mohamed GA, Mohamed Saleem MA, Ognjenovic NB, Lu H, Kolling FW, Wilkins OM, Das S, LaCroix IS, Nagaraj SH, Muller KE, Gerber SA, Miller TW, Pattabiraman DR |date=April 2024 |title=Pharmacological induction of chromatin remodeling drives chemosensitization in triple-negative breast cancer |journal=Cell Reports. Medicine |volume=5 |issue=4 |article-number=101504 |doi=10.1016/j.xcrm.2024.101504 |pmc=11031425 |pmid=38593809}}</ref><ref>{{cite journal |vauthors=Bagheri M, Lee MK, Muller KE, Miller TW, Pattabiraman DR, Christensen BC |date=March 2024 |title=Alteration of DNA methyltransferases by eribulin elicits broad DNA methylation changes with potential therapeutic implications for triple-negative breast cancer |journal=Epigenomics |volume=16 |issue=5 |pages=293–308 |doi=10.2217/epi-2023-0339 |pmc=10910603 |pmid=38356412}}</ref>

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.<ref name=":0" /><ref name=":1" /><ref>{{cite journal | vauthors = Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C | title = Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study | journal = Lancet | volume = 377 | issue = 9769 | pages = 914–923 | date = March 2011 | pmid = 21376385 | doi = 10.1016/S0140-6736(11)60070-6 | url = https://pubmed.ncbi.nlm.nih.gov/21376385 }}</ref> A 2014 study found that post-taxane eribulin resistance is due to expression of the P-glycoprotein (PgP) multidrug resistance protein 1 (MDR1).<ref name="pmid25378644">{{cite journal | vauthors = Laughney AM, Kim E, Sprachman MM, Miller MA, Kohler RH, Yang KS, Orth JD, Mitchison TJ, Weissleder R | date = November 2014 | title = Single-cell pharmacokinetic imaging reveals a therapeutic strategy to overcome drug resistance to the microtubule inhibitor eribulin | journal = Science Translational Medicine | volume = 6 | issue = 261 | page = 261ra152 | doi = 10.1126/scitranslmed.3009318 | pmc = 4330962 | pmid = 25378644 }}</ref> Eribulin had previously been shown to be a PgP substrate with the ability to inhibit PgP-mediated drug efflux in cell-based efflux models.<ref>{{cite journal |vauthors=Taur JS, DesJardins CS, Schuck EL, Wong YN |date=April 2011 |title=Interactions between the chemotherapeutic agent eribulin mesylate (E7389) and P-glycoprotein in CF-1 abcb1a-deficient mice and Caco-2 cells |journal=Xenobiotica; The Fate of Foreign Compounds in Biological Systems |volume=41 |issue=4 |pages=320–326 |doi=10.3109/00498254.2010.542256 |pmid=21162698}}</ref> Fluorescently labeled eribulin has been used to study the pharmacokinetics and pharmacodynamics at single cell level ''in vivo''.<ref name="pmid25378644" />

Eribulin's chemical structure (as ER-086526) was originally published in 2001,<ref name="pmid11221827" /> and its synthesis was first published in 2004.<ref>{{cite journal |vauthors=Zheng W, Seletsky BM, Palme MH, Lydon PJ, Singer LA, Chase CE, Lemelin CA, Shen Y, Davis H, Tremblay L, Towle MJ, Salvato KA, Wels BF, Aalfs KK, Kishi Y, Littlefield BA, Yu MJ |date=November 2004 |title=Macrocyclic ketone analogues of halichondrin B |journal=Bioorganic & Medicinal Chemistry Letters |volume=14 |issue=22 |pages=5551–5554 |doi=10.1016/j.bmcl.2004.08.069 |pmid=15482922}}</ref>

== 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''.<ref name="Hirata_1986" /> 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.<ref>{{cite journal | vauthors = Aicher TD, Buszek KR, Fang FG, Forsyth CJ, Jung SH, Kishi Y, Matelich MC, Scola PM, Spero DM, Yoon SK | date = April 1992 | title = Total synthesis of halichondrin B and norhalichondrin B | journal = Journal of the American Chemical Society | volume = 114 | issue = 8 | pages = 3162–3164 | doi = 10.1021/ja00034a086 | issn = 0002-7863 }}</ref> 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.<ref name="Hirata_1986" /> 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<ref name="isbn0-8493-1863-7" /> (see also footnote 3 of Towle et al., 2001<ref name="pmid11221827" />). 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<ref name="pmid11221827" /> (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, '''ERI'''bulin. Eribulin's potent ''in vitro'' and ''in vivo'' anticancer activity, first shown by ERI scientists,<ref name="pmid11221827" /> was subsequently confirmed by the U.S. National Cancer Institute (NCI)<ref>{{cite journal | vauthors = Dabydeen DA, Burnett JC, Bai R, Verdier-Pinard P, Hickford SJ, Pettit GR, Blunt JW, Munro MH, Gussio R, Hamel E | title = 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 | journal = Molecular Pharmacology | volume = 70 | issue = 6 | pages = 1866–1875 | date = December 2006 | pmid = 16940412 | doi = 10.1124/mol.106.026641 }}</ref> 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,<ref>{{cite journal | vauthors = Synold TW, Morgan RJ, Newman EM, Lenz HJ, Gandara DR, Colevas AD, Lewis MD, Doroshow JH | date = June 2005 | title = A phase I pharmacokinetic and target validation study of the novel anti-tubulin agent E7389: A California Cancer Consortium trial | journal = Journal of Clinical Oncology | volume = 23 | issue = 16_suppl | pages = 3036–3036 | doi = 10.1200/jco.2005.23.16_suppl.3036 | issn = 0732-183X }}</ref><ref>{{cite journal | vauthors = Morgan RJ, Synold TW, Longmate JA, Quinn DI, Gandara D, Lenz HJ, Ruel C, Xi B, Lewis MD, Colevas AD, Doroshow J, Newman EM | title = 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 | journal = Cancer Chemotherapy and Pharmacology | volume = 76 | issue = 5 | pages = 897–907 | date = November 2015 | pmid = 26362045 | doi = 10.1007/s00280-015-2868-7 | pmc = 4694049 | url = https://pubmed.ncbi.nlm.nih.gov/26362045 }}</ref> established the still-current dosing schedule of 1.4 mg/m<sup>2</sup> on days 1 and 8 of a 21-day cycle.<ref name=":0" /> 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.<ref>{{cite web | title = 64 studies currently listed as recruiting or not yet recruiting for eribulin or E7389 as of 4-28-2026. Does not include completed studies. | url = http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389 | work = clinicaltrials.gov | publisher = U.S. National Library of Medicine|access-date=April 28, 2026}}</ref>

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.<ref>{{ClinicalTrialsGov|NCT03207672|Study of E7389 Liposomal Formulation in Subjects With Solid Tumor}}</ref> Preliminary ''in vivo'' experiments show a decrease in C(max) and a longer half-life with the liposomal formulation.<ref name=pmid23313921>{{cite journal | vauthors = Yu Y, Desjardins C, Saxton P, Lai G, Schuck E, Wong YN | title = Characterization of the pharmacokinetics of a liposomal formulation of eribulin mesylate (E7389) in mice | journal = International Journal of Pharmaceutics | volume = 443 | issue = 1–2 | pages = 9–16 | date = February 2013 | pmid = 23313921 | doi = 10.1016/j.ijpharm.2013.01.010 }}</ref> 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.<ref>{{ClinicalTrialsGov|NCT03222856|Ph II Study of Pembrolizumab & Eribulin in Patients With HR+/HER2- MBC Previously Treated With Anthracyclines & Taxanes (KELLY)}}</ref>

== References == {{reflist}}

Category:Antineoplastic drugs Category:Macrocycles Category:Orphan drugs Category:Tetrahydropyrans Category:Tetrahydrofurans Category:Methoxy compounds Category:Amines