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

被引：41

作者：

Fanning, S. W. ^{[1
]}

Hodges-Gallagher, L. ^{[2
]}

Myles, D. C. ^{[2
]}

Sun, R. ^{[2
]}

Fowler, C. E. ^{[1
]}

Plant, I. N. ^{[3
]}

Green, B. D. ^{[1
]}

Harmon, C. L. ^{[2
]}

Greene, G. L. ^{[1
]}

Kushner, P. J. ^{[2
]}

机构：

[1] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA

[2] Olema Pharmaceut, San Francisco, CA 94107 USA

[3] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

BREAST-TUMORS; ER-ALPHA; PROMOTER-CONTEXT; FULVESTRANT; BINDING; MECHANISMS; RESISTANCE; ANTAGONISM; GROWTH; BONE;

D O I：

10.1038/s41467-018-04413-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

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