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dc.contributor.authorPuyang, X
dc.contributor.authorFurman, C
dc.contributor.authorZheng, GZ
dc.contributor.authorWu, ZJ
dc.contributor.authorBanka, D
dc.contributor.authorAithal, K
dc.contributor.authorAgoulnik, S
dc.contributor.authorBolduc, DM
dc.contributor.authorBuonamici, S
dc.contributor.authorCaleb, B
dc.contributor.authorDas, S
dc.contributor.authorEckley, S
dc.contributor.authorFekkes, P
dc.contributor.authorHao, M-H
dc.contributor.authorHart, A
dc.contributor.authorHoutman, R
dc.contributor.authorIrwin, S
dc.contributor.authorJoshi, JJ
dc.contributor.authorKarr, C
dc.contributor.authorKim, A
dc.contributor.authorKumar, N
dc.contributor.authorKumar, P
dc.contributor.authorKuznetsov, G
dc.contributor.authorLai, WG
dc.contributor.authorLarsen, N
dc.contributor.authorMackenzie, C
dc.contributor.authorMartin, L-A
dc.contributor.authorMelchers, D
dc.contributor.authorMoriarty, A
dc.contributor.authorNguyen, T-V
dc.contributor.authorNorris, J
dc.contributor.authorO'Shea, M
dc.contributor.authorPancholi, S
dc.contributor.authorPrajapati, S
dc.contributor.authorRajagopalan, S
dc.contributor.authorReynolds, DJ
dc.contributor.authorRimkunas, V
dc.contributor.authorRioux, N
dc.contributor.authorRibas, R
dc.contributor.authorSiu, A
dc.contributor.authorSivakumar, S
dc.contributor.authorSubramanian, V
dc.contributor.authorThomas, M
dc.contributor.authorVaillancourt, FH
dc.contributor.authorWang, J
dc.contributor.authorWardell, S
dc.contributor.authorWick, MJ
dc.contributor.authorYao, S
dc.contributor.authorYu, L
dc.contributor.authorWarmuth, M
dc.contributor.authorSmith, PG
dc.contributor.authorZhu, P
dc.contributor.authorKorpal, M
dc.date.accessioned2018-11-14T09:08:40Z
dc.date.issued2018-09
dc.identifier.citationCancer discovery, 2018, 8 (9), pp. 1176 - 1193
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2923
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.cd-17-1229
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). <i>In vitro</i> comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERα<sup>WT</sup> and ERα<sup>MUT</sup> cell lines. <i>In vivo</i>, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERα<sup>WT</sup> and ERα<sup>Y537S</sup> 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 ERα<sup>WT</sup> and ERα<sup>MUT</sup> 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.<b>Significance:</b> Nearly 30% of endocrine therapy-resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERα<sup>WT</sup> and ERα<sup>MUT</sup>, promotes a unique antagonist conformation, and demonstrates improved <i>in vitro</i> and <i>in vivo</i> activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. <i>Cancer Discov; 8(9); 1176-93. ©2018 AACR.</i><i>This article is highlighted in the In This Issue feature, p. 1047</i>.
dc.formatPrint-Electronic
dc.format.extent1176 - 1193
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectBreast Neoplasms
dc.subjectCysteine
dc.subjectIndazoles
dc.subjectEstrogen Receptor alpha
dc.subjectProtein Kinase Inhibitors
dc.subjectDrug Screening Assays, Antitumor
dc.subjectAdministration, Oral
dc.subjectXenograft Model Antitumor Assays
dc.subjectCell Proliferation
dc.subjectCell Survival
dc.subjectProtein Conformation
dc.subjectDrug Synergism
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectFemale
dc.subjectMCF-7 Cells
dc.subjectEstrogen Receptor Antagonists
dc.titleDiscovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERα<sup>WT</sup> and ERα<sup>MUT</sup> Breast Cancer.
dc.typeJournal Article
dcterms.dateAccepted2018-06-19
rioxxterms.versionofrecord10.1158/2159-8290.cd-17-1229
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2018-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer discovery
pubs.issue9
pubs.notesNot known
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.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-statusPublished
pubs.volume8en_US
pubs.embargo.termsNot known
icr.researchteamEndocrinologyen_US
dc.contributor.icrauthorMartin, Lesley-Annen
dc.contributor.icrauthorPancholi, Sunilen


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