Etacstil Explained

Iupac Name:(2E)-3-acrylic acid
Cas Number:155701-61-4
Unii:WEM4BUT8FL
Pubchem:5288494
Chembl:33899
Chemspiderid:4450668
C:25
H:22
O:2
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.[1] [2] [3] 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.[4] [5] [6] [7] [8] Etacstil is a tamoxifen derivative and one of the first drugs to overcome tamoxifen-resistance. It is the predecessor of GW-7604,[9] of which etacstil is a prodrug (GW-7604 being the 4-hydroxy metabolite of etacstil).[10] 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.[11] [12] 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.[6] [13] [11]

After many dormant years, a recent resurgence of interest in SERDs has led to the development of brilanestrant, a structural analogue of etacstil.[13]

See also

Notes and References

  1. Book: Cancer Chemoprevention: Volume 2: Strategies for Cancer Chemoprevention. 9781592597680. Kelloff GJ, Hawk ET, Sigman CC . 2008-08-17. Springer .
  2. Web site: GW 5638 Profile . AdisInsight . Springer Nature Switzerland AG .
  3. GW 5638 . Nuclear Receptor Signaling Atlas.. 10.1621/B4A9CIQ78V. Becnel LB, Darlington YF, Orechsner S, Easton-Marks J, Watkins CA, McOwiti A, Kankanamge WH, Dehart M, Silva CM, Margolis RN, McKenna NJ . 6 .
  4. 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.Connor CE, Norris JD, Broadwater G, Willson TM, Gottardis MM, Dewhirst MW, McDonnell DP . Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor . Cancer Research . 61 . 7 . 2917–2922 . April 2001 . 11306468 . Mark Dewhirst .
  5. Web site: GW5638 uniquely alters the shape of the estrogen receptor . 2015 . The Ben May Department for Cancer Research . The University of Chicago . https://web.archive.org/web/20151010070838/http://benmay.uchicago.edu/page/news-archive-year-2005-GW5638 . 10 October 2015 .
  6. Web site: Tamoxifen-like drug suggests new ways to selectively block estrogen. . 12 May 2005 . The University of Chicago Medical Center . 2016-10-25. 2018-03-27. https://web.archive.org/web/20180327181926/http://www.uchospitals.edu/news/2005/20050512-gw5638.html. dead.
  7. Dardes RC, O'Regan RM, Gajdos C, Robinson SP, Bentrem D, De Los Reyes A, Jordan VC . Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo . Clinical Cancer Research . 8 . 6 . 1995–2001 . June 2002 . 12060645 .
  8. Tong S, Chen Q, Shan SQ, Dewhirst MW, Yuan F . Quantitative comparison of the inhibitory effects of GW5638 and tamoxifen on angiogenesis in the cornea pocket assay . Angiogenesis . 9 . 2 . 53–58 . 2006 . 16622786 . 10.1007/s10456-006-9029-x . 35414830 .
  9. Bentrem D, Dardes R, Liu H, MacGregor-Schafer J, Zapf J, Jordan V . Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen . Endocrinology . 142 . 2 . 838–846 . February 2001 . 11159857 . 10.1210/endo.142.2.7932 . free .
  10. Bentrem D, Dardes R, Liu H, MacGregor-Schafer J, Zapf J, Jordan V . Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen . Endocrinology . 142 . 2 . 838–846 . February 2001 . 11159857 . 10.1210/endo.142.2.7932 . free .
  11. Web site: Osteoporosis Drug Bazedoxifene Stops Growth Of Breast Cancer Cells . 17 June 2013 . Medical News Today . https://web.archive.org/web/20140108094230/http://www.medicalnewstoday.com/articles/262039.php . 8 January 2014 .
  12. Willson TM, Henke BR, Momtahen TM, Charifson PS, Batchelor KW, Lubahn DB, Moore LB, Oliver BB, Sauls HR, Triantafillou JA . 6 . 3-[4-(1,2-Diphenylbut-1-enyl)phenyl]acrylic acid: a non-steroidal estrogen with functional selectivity for bone over uterus in rats . Journal of Medicinal Chemistry . 37 . 11 . 1550–1552 . May 1994 . 8201587 . 10.1021/jm00037a002 .
  13. Wardell SE, Nelson ER, Chao CA, Alley HM, McDonnell DP . Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader . Endocrine-Related Cancer . 22 . 5 . 713–724 . October 2015 . 26162914 . 4545300 . 10.1530/ERC-15-0287 .

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