دورية أكاديمية
Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.
| العنوان: | Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer. |
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| المؤلفون: | Puyang, X, Furman, C, Zheng, GZ, Wu, ZJ, Banka, D, Aithal, K, Agoulnik, S, Bolduc, DM, Buonamici, S, Caleb, B, Das, S, Eckley, S, Fekkes, P, Hao, M-H, Hart, A, Houtman, R, Irwin, S, Joshi, JJ, Karr, C, Kim, A, Kumar, N, Kumar, P, Kuznetsov, G, Lai, WG, Larsen, N, Mackenzie, C, Martin, L-A, Melchers, D, Moriarty, A, Nguyen, T-V, Norris, J, O'Shea, M, Pancholi, S, Prajapati, S, Rajagopalan, S, Reynolds, DJ, Rimkunas, V, Rioux, N, Ribas, R, Siu, A, Sivakumar, S, Subramanian, V, Thomas, M, Vaillancourt, FH, Wang, J, Wardell, S, Wick, MJ, Yao, S, Yu, L, Warmuth, M, Smith, PG, Zhu, P, Korpal, M |
| المساهمون: | Martin, Lesley-Ann, Pancholi, Sunil |
| بيانات النشر: | AMER ASSOC CANCER RESEARCH |
| سنة النشر: | 2018 |
| المجموعة: | The Institute of Cancer Research (ICR): Publications Repository |
| مصطلحات موضوعية: | Cell Line, Tumor, Animals, Humans, Mice, Breast Neoplasms, Cysteine, Indazoles, Estrogen Receptor alpha, Protein Kinase Inhibitors, Drug Screening Assays, Antitumor, Administration, Oral, Xenograft Model Antitumor Assays, Cell Proliferation, Cell Survival, Protein Conformation, Drug Synergism, Drug Resistance, Neoplasm, Mutation, Female, MCF-7 Cells, Estrogen Receptor Antagonists |
| الوصف: | 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). 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Print-Electronic; 1193; application/pdf |
| اللغة: | English |
| تدمد: | 2159-8274 2159-8290 |
| العلاقة: | Cancer discovery, 2018, 8 (9), pp. 1176 - 1193; https://repository.icr.ac.uk/handle/internal/2923Test |
| DOI: | 10.1158/2159-8290.cd-17-1229 |
| الإتاحة: | https://doi.org/10.1158/2159-8290.cd-17-1229Test https://repository.icr.ac.uk/handle/internal/2923Test |
| حقوق: | https://www.rioxx.net/licenses/under-embargo-all-rights-reservedTest |
| رقم الانضمام: | edsbas.21FFE31 |
| قاعدة البيانات: | BASE |
| تدمد: | 21598274 21598290 |
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| DOI: | 10.1158/2159-8290.cd-17-1229 |