dc.contributor.author | Puyang, X | |
dc.contributor.author | Furman, C | |
dc.contributor.author | Zheng, GZ | |
dc.contributor.author | Wu, ZJ | |
dc.contributor.author | Banka, D | |
dc.contributor.author | Aithal, K | |
dc.contributor.author | Agoulnik, S | |
dc.contributor.author | Bolduc, DM | |
dc.contributor.author | Buonamici, S | |
dc.contributor.author | Caleb, B | |
dc.contributor.author | Das, S | |
dc.contributor.author | Eckley, S | |
dc.contributor.author | Fekkes, P | |
dc.contributor.author | Hao, M-H | |
dc.contributor.author | Hart, A | |
dc.contributor.author | Houtman, R | |
dc.contributor.author | Irwin, S | |
dc.contributor.author | Joshi, JJ | |
dc.contributor.author | Karr, C | |
dc.contributor.author | Kim, A | |
dc.contributor.author | Kumar, N | |
dc.contributor.author | Kumar, P | |
dc.contributor.author | Kuznetsov, G | |
dc.contributor.author | Lai, WG | |
dc.contributor.author | Larsen, N | |
dc.contributor.author | Mackenzie, C | |
dc.contributor.author | Martin, L-A | |
dc.contributor.author | Melchers, D | |
dc.contributor.author | Moriarty, A | |
dc.contributor.author | Nguyen, T-V | |
dc.contributor.author | Norris, J | |
dc.contributor.author | O'Shea, M | |
dc.contributor.author | Pancholi, S | |
dc.contributor.author | Prajapati, S | |
dc.contributor.author | Rajagopalan, S | |
dc.contributor.author | Reynolds, DJ | |
dc.contributor.author | Rimkunas, V | |
dc.contributor.author | Rioux, N | |
dc.contributor.author | Ribas, R | |
dc.contributor.author | Siu, A | |
dc.contributor.author | Sivakumar, S | |
dc.contributor.author | Subramanian, V | |
dc.contributor.author | Thomas, M | |
dc.contributor.author | Vaillancourt, FH | |
dc.contributor.author | Wang, J | |
dc.contributor.author | Wardell, S | |
dc.contributor.author | Wick, MJ | |
dc.contributor.author | Yao, S | |
dc.contributor.author | Yu, L | |
dc.contributor.author | Warmuth, M | |
dc.contributor.author | Smith, PG | |
dc.contributor.author | Zhu, P | |
dc.contributor.author | Korpal, M | |
dc.date.accessioned | 2018-11-14T09:08:40Z | |
dc.date.issued | 2018-09 | |
dc.identifier.citation | Cancer discovery, 2018, 8 (9), pp. 1176 - 1193 | |
dc.identifier.issn | 2159-8274 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/2923 | |
dc.identifier.eissn | 2159-8290 | |
dc.identifier.doi | 10.1158/2159-8290.cd-17-1229 | |
dc.description.abstract | Mutations 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.format | Print-Electronic | |
dc.format.extent | 1176 - 1193 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Breast Neoplasms | |
dc.subject | Cysteine | |
dc.subject | Indazoles | |
dc.subject | Estrogen Receptor alpha | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Drug Screening Assays, Antitumor | |
dc.subject | Administration, Oral | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Cell Proliferation | |
dc.subject | Cell Survival | |
dc.subject | Protein Conformation | |
dc.subject | Drug Synergism | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Mutation | |
dc.subject | Female | |
dc.subject | MCF-7 Cells | |
dc.subject | Estrogen Receptor Antagonists | |
dc.title | Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERα<sup>WT</sup> and ERα<sup>MUT</sup> Breast Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-06-19 | |
rioxxterms.versionofrecord | 10.1158/2159-8290.cd-17-1229 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2018-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer discovery | |
pubs.issue | 9 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 8 | en_US |
pubs.embargo.terms | Not known | |
icr.researchteam | Endocrinology | en_US |
dc.contributor.icrauthor | Martin, Lesley-Ann | en |
dc.contributor.icrauthor | Pancholi, Sunil | en |