Etacstil
{{Short description|Chemical compound}}
{{Infobox drug
| IUPAC_name = (2E)-3-
| image = Etacstil skeletal.svg
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| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 155701-61-4
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = WEM4BUT8FL
| ATCvet =
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| PubChem = 5288494
| DrugBank =
| ChEMBL = 33899
| ChemSpiderID = 4450668
| chemical_formula =
| C=25 | H=22 | O=2
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| smiles = CC/C(=C(\c1ccccc1)/c2ccc(cc2)/C=C/C(=O)O)/c3ccccc3
| StdInChI=1S/C25H22O2/c1-2-23(20-9-5-3-6-10-20)25(21-11-7-4-8-12-21)22-16-13-19(14-17-22)15-18-24(26)27/h3-18H,2H2,1H3,(H,26,27)/b18-15+,25-23-
| StdInChIKey = HJQQVNIORAQATK-DDJBQNAASA-N
}}
Etacstil (developmental code names GW-5638, DPC974) is an orally active, nonsteroidal, combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was developed for the treatment of estrogen receptor-positive breast cancer.{{Cite book |url=https://books.google.com/books?id=ldyg4-cem9UC&pg=PA251 |title=Cancer Chemoprevention: Volume 2: Strategies for Cancer Chemoprevention |vauthors=Kelloff GJ, Hawk ET, Sigman CC |date=2008-08-17 |publisher=Springer |isbn=9781592597680}}{{Cite web |title=GW 5638 Profile |url=http://adisinsight.springer.com/drugs/800010109 |website=AdisInsight |publisher=Springer Nature Switzerland AG}}{{Cite journal |display-authors=6 |vauthors=Becnel LB, Darlington YF, Orechsner S, Easton-Marks J, Watkins CA, McOwiti A, Kankanamge WH, Dehart M, Silva CM, Margolis RN, McKenna NJ |title=GW 5638 |journal=Nuclear Receptor Signaling Atlas |doi=10.1621/B4A9CIQ78V}} It was shown to overcome antiestrogen (tamoxifen, aromatase inhibitor, fulvestrant) resistance in breast cancer by altering the shape of the estrogen receptor, thus exhibiting SERD properties.Antiestrogen GW5638 induces a unique structural change in the ER. The biological significance of this conformational change was revealed in studies that demonstrated that tamoxifen-resistant breast tumor explants are not cross-resistant to GW5638. Because of these properties, this drug is currently being developed as a potential therapeutic for tamoxifen-resistant breast cancers.{{Cite journal |author-link6=Mark Dewhirst |vauthors=Connor CE, Norris JD, Broadwater G, Willson TM, Gottardis MM, Dewhirst MW, McDonnell DP |date=April 2001 |title=Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor |journal=Cancer Research |volume=61 |issue=7 |pages=2917–2922 |pmid=11306468}}{{Cite web |date=2015 |title=GW5638 uniquely alters the shape of the estrogen receptor |url=http://benmay.uchicago.edu/page/news-archive-year-2005-GW5638 |archive-url=https://web.archive.org/web/20151010070838/http://benmay.uchicago.edu/page/news-archive-year-2005-GW5638 |archive-date=10 October 2015 |website=The Ben May Department for Cancer Research |publisher=The University of Chicago}}{{Cite web |date=12 May 2005 |title=Tamoxifen-like drug suggests new ways to selectively block estrogen. |url=http://www.uchospitals.edu/news/2005/20050512-gw5638.html |url-status=dead |archive-url=https://web.archive.org/web/20180327181926/http://www.uchospitals.edu/news/2005/20050512-gw5638.html |archive-date=2018-03-27 |access-date=2016-10-25 |website=The University of Chicago Medical Center}}{{Cite journal |vauthors=Dardes RC, O'Regan RM, Gajdos C, Robinson SP, Bentrem D, De Los Reyes A, Jordan VC |date=June 2002 |title=Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo |journal=Clinical Cancer Research |volume=8 |issue=6 |pages=1995–2001 |pmid=12060645}}{{Cite journal |vauthors=Tong S, Chen Q, Shan SQ, Dewhirst MW, Yuan F |year=2006 |title=Quantitative comparison of the inhibitory effects of GW5638 and tamoxifen on angiogenesis in the cornea pocket assay |journal=Angiogenesis |volume=9 |issue=2 |pages=53–58 |doi=10.1007/s10456-006-9029-x |pmid=16622786 |s2cid=35414830}} Etacstil is a tamoxifen derivative and one of the first drugs to overcome tamoxifen-resistance. It is the predecessor of GW-7604,{{Cite journal |vauthors=Bentrem D, Dardes R, Liu H, MacGregor-Schafer J, Zapf J, Jordan V |date=February 2001 |title=Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen |journal=Endocrinology |volume=142 |issue=2 |pages=838–846 |doi=10.1210/endo.142.2.7932 |pmid=11159857 |doi-access=free}} of which etacstil is a prodrug (GW-7604 being the 4-hydroxy metabolite of etacstil).{{Cite journal |vauthors=Bentrem D, Dardes R, Liu H, MacGregor-Schafer J, Zapf J, Jordan V |date=February 2001 |title=Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen |journal=Endocrinology |volume=142 |issue=2 |pages=838–846 |doi=10.1210/endo.142.2.7932 |pmid=11159857 |doi-access=free}} This is analogous to the case of tamoxifen being a prodrug of afimoxifene (4-hydroxytamoxifen).
Etacstil was developed in the early 1990s by Duke University, Glaxo Wellcome, and later, Dupont.{{Cite web |date=17 June 2013 |title=Osteoporosis Drug Bazedoxifene Stops Growth Of Breast Cancer Cells |url=http://www.medicalnewstoday.com/articles/262039.php |archive-url=https://web.archive.org/web/20140108094230/http://www.medicalnewstoday.com/articles/262039.php |archive-date=8 January 2014 |website=Medical News Today}}{{Cite journal |display-authors=6 |vauthors=Willson TM, Henke BR, Momtahen TM, Charifson PS, Batchelor KW, Lubahn DB, Moore LB, Oliver BB, Sauls HR, Triantafillou JA |date=May 1994 |title=3-[4-(1,2-Diphenylbut-1-enyl)phenyl]acrylic acid: a non-steroidal estrogen with functional selectivity for bone over uterus in rats |journal=Journal of Medicinal Chemistry |volume=37 |issue=11 |pages=1550–1552 |doi=10.1021/jm00037a002 |pmid=8201587}} In 2001, Bristol Myers-Squibb (BMS) acquired Dupont, and for non-scientific, corporate reasons, closed the trial and abandoned the release of etacstil and its metabolite GW-7604.{{Cite journal |vauthors=Wardell SE, Nelson ER, Chao CA, Alley HM, McDonnell DP |date=October 2015 |title=Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader |journal=Endocrine-Related Cancer |volume=22 |issue=5 |pages=713–724 |doi=10.1530/ERC-15-0287 |pmc=4545300 |pmid=26162914}}
After many dormant years, a recent resurgence of interest in SERDs has led to the development of brilanestrant, a structural analogue of etacstil.