2. Academic Validation
  3. Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity

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

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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