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

  • Nat Commun. 2018 Jun 18;9(1):2368. doi: 10.1038/s41467-018-04413-3.
S W Fanning  1 ,  L Hodges-Gallagher  2 ,  D C Myles  3 ,  R Sun  3 ,  C E Fowler  4 ,  I N Plant  5 ,  B D Green  4 ,  C L Harmon  3 ,  G L Greene  4 ,  P J Kushner  3
Affiliations
  • 1. Ben May Department for Cancer Research, University of Chicago, Chicago, IL, 60637, USA. [email protected].
  • 2. Olema Pharmaceuticals, San Francisco, CA, 94107, USA. [email protected].
  • 3. Olema Pharmaceuticals, San Francisco, CA, 94107, USA.
  • 4. Ben May Department for Cancer Research, University of Chicago, Chicago, IL, 60637, USA.
  • 5. Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA.
PMID: 29915250 DOI: 10.1038/s41467-018-04413-3
Abstract

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.

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