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Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity

Journal Article · · Nature Communications
 [1];  [2];  [2];  [2];  [1];  [3];  [1];  [2];  [1];  [2]
  1. Univ. of Chicago, IL (United States)
  2. Olema Pharmaceuticals, San Francisco, CA (United States)
  3. Harvard Medical School, Boston, MA (United States)
+ Show Author Affiliations
Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
Susan G. Komen Foundation; USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); Virginia and D.K. Ludwig Fund for Cancer Research
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1511719
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 9; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (4)

Discovery of novel natural compound inhibitors targeting estrogen receptor α by an integrated virtual screening strategy journal August 2019
Emerging modes-of-action in drug discovery journal January 2019
Next-Generation ERα Inhibitors for Endocrine-Resistant ER+ Breast Cancer journal February 2019
Ligand-Based Drug Design: Synthesis and Biological Evaluation of Substituted Benzoin Derivatives as Potential Antitumor Agents journal May 2019

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Related Subjects

60 APPLIED LIFE SCIENCES
Breast cancer
Drug development