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Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.

Publication ,  Journal Article
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 ...
Published in: Cancer Discov
September 2018

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.

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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

September 2018

Volume

8

Issue

9

Start / End Page

1176 / 1193

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Protein Kinase Inhibitors
  • Protein Conformation
  • Mutation
  • Mice
  • MCF-7 Cells
  • Indazoles
  • Humans
  • Female
  • Estrogen Receptor alpha
 

Citation

APA
Chicago
ICMJE
MLA
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Puyang, X., Furman, C., Zheng, G. Z., Wu, Z. J., Banka, D., Aithal, K., … Korpal, M. (2018). Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer. Cancer Discov, 8(9), 1176–1193. https://doi.org/10.1158/2159-8290.CD-17-1229
Puyang, Xiaoling, Craig Furman, Guo Zhu Zheng, Zhenhua J. Wu, Deepti Banka, Kiran Aithal, Sergei Agoulnik, et al. “Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.Cancer Discov 8, no. 9 (September 2018): 1176–93. https://doi.org/10.1158/2159-8290.CD-17-1229.
Puyang X, Furman C, Zheng GZ, Wu ZJ, Banka D, Aithal K, et al. Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer. Cancer Discov. 2018 Sep;8(9):1176–93.
Puyang, Xiaoling, et al. “Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.Cancer Discov, vol. 8, no. 9, Sept. 2018, pp. 1176–93. Pubmed, doi:10.1158/2159-8290.CD-17-1229.
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. Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer. Cancer Discov. 2018 Sep;8(9):1176–1193.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

September 2018

Volume

8

Issue

9

Start / End Page

1176 / 1193

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Protein Kinase Inhibitors
  • Protein Conformation
  • Mutation
  • Mice
  • MCF-7 Cells
  • Indazoles
  • Humans
  • Female
  • Estrogen Receptor alpha