Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.
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Date
2018-09-01Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
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
Research team
Endocrinology
Language
eng
Date accepted
2018-06-19
License start date
2018-09
Citation
Cancer discovery, 2018, 8 (9), pp. 1176 - 1193
Publisher
AMER ASSOC CANCER RESEARCH