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dc.contributor.authorPuyang, Xen_US
dc.contributor.authorFurman, Cen_US
dc.contributor.authorZheng, GZen_US
dc.contributor.authorWu, ZJen_US
dc.contributor.authorBanka, Den_US
dc.contributor.authorAithal, Ken_US
dc.contributor.authorAgoulnik, Sen_US
dc.contributor.authorBolduc, DMen_US
dc.contributor.authorBuonamici, Sen_US
dc.contributor.authorCaleb, Ben_US
dc.contributor.authorDas, Sen_US
dc.contributor.authorEckley, Sen_US
dc.contributor.authorFekkes, Pen_US
dc.contributor.authorHao, M-Hen_US
dc.contributor.authorHart, Aen_US
dc.contributor.authorHoutman, Ren_US
dc.contributor.authorIrwin, Sen_US
dc.contributor.authorJoshi, JJen_US
dc.contributor.authorKarr, Cen_US
dc.contributor.authorKim, Aen_US
dc.contributor.authorKumar, Nen_US
dc.contributor.authorKumar, Pen_US
dc.contributor.authorKuznetsov, Gen_US
dc.contributor.authorLai, WGen_US
dc.contributor.authorLarsen, Nen_US
dc.contributor.authorMackenzie, Cen_US
dc.contributor.authorMartin, L-Aen_US
dc.contributor.authorMelchers, Den_US
dc.contributor.authorMoriarty, Aen_US
dc.contributor.authorNguyen, T-Ven_US
dc.contributor.authorNorris, Jen_US
dc.contributor.authorO'Shea, Men_US
dc.contributor.authorPancholi, Sen_US
dc.contributor.authorPrajapati, Sen_US
dc.contributor.authorRajagopalan, Sen_US
dc.contributor.authorReynolds, DJen_US
dc.contributor.authorRimkunas, Ven_US
dc.contributor.authorRioux, Nen_US
dc.contributor.authorRibas, Ren_US
dc.contributor.authorSiu, Aen_US
dc.contributor.authorSivakumar, Sen_US
dc.contributor.authorSubramanian, Ven_US
dc.contributor.authorThomas, Men_US
dc.contributor.authorVaillancourt, FHen_US
dc.contributor.authorWang, Jen_US
dc.contributor.authorWardell, Sen_US
dc.contributor.authorWick, MJen_US
dc.contributor.authorYao, Sen_US
dc.contributor.authorYu, Len_US
dc.contributor.authorWarmuth, Men_US
dc.contributor.authorSmith, PGen_US
dc.contributor.authorZhu, Pen_US
dc.contributor.authorKorpal, Men_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2018-11-14T09:08:40Z
dc.date.issued2018-09en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/29991605en_US
dc.identifier2159-8290.CD-17-1229en_US
dc.identifier.citationCancer Discov, 2018, 8 (9), pp. 1176 - 1193en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2923
dc.identifier.eissn2159-8290en_US
dc.identifier.doi10.1158/2159-8290.CD-17-1229en_US
dc.description.abstractMutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERα antagonists referred to as selective estrogen receptor covalent antagonists (SERCA). In vitro comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERαWT and ERαMUT cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERαWT and ERαY537S breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERαWT and ERαMUT cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERα covalent antagonists with an improved profile over SoCs.Significance: Nearly 30% of endocrine therapy-resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERαWT and ERαMUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. Cancer Discov; 8(9); 1176-93. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.en_US
dc.format.extent1176 - 1193en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.titleDiscovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-06-19en_US
rioxxterms.versionofrecord10.1158/2159-8290.CD-17-1229en_US
rioxxterms.licenseref.startdate2018-09en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfCancer Discoven_US
pubs.issue9en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.publication-statusPublisheden_US
pubs.volume8en_US
pubs.embargo.termsNot knownen_US
icr.researchteamEndocrinologyen_US
dc.contributor.icrauthorMartin, Lesley-Annen_US


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