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

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 and P. J. Kushner
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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

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04413-3

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