Fanning, S. W.Hodges-Gallagher, L.Myles, D. C.Sun, R.Fowler, C. E.Plant, I. N.Green, B. D.Harmon, C. L.Greene, G. L.Kushner, P. J.2018-07-252018Fanning, S. W., 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. 2018. “Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity.” Nature Communications 9 (1): 2368. doi:10.1038/s41467-018-04413-3. http://dx.doi.org/10.1038/s41467-018-04413-3.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37298423Complex 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.en-USJournal Article2018-07-2510.1038/s41467-018-04413-3