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

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  • S. W. Fanning

    (University of Chicago)

  • L. Hodges-Gallagher

    (Olema Pharmaceuticals)

  • D. C. Myles

    (Olema Pharmaceuticals)

  • R. Sun

    (Olema Pharmaceuticals)

  • C. E. Fowler

    (University of Chicago)

  • I. N. Plant

    (Harvard Medical School)

  • B. D. Green

    (University of Chicago)

  • C. L. Harmon

    (Olema Pharmaceuticals)

  • G. L. Greene

    (University of Chicago)

  • P. J. Kushner

    (Olema Pharmaceuticals)

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.

Suggested Citation

  • S. W. Fanning & L. Hodges-Gallagher & D. C. Myles & R. Sun & C. E. Fowler & I. N. Plant & B. D. Green & C. L. Harmon & G. L. Greene & P. J. Kushner, 2018. "Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04413-3
    DOI: 10.1038/s41467-018-04413-3
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