Etacstil

Last updated
Etacstil
Etacstil skeletal.svg
Identifiers
  • (2E)-3-{4-[(1Z)-1,2-Diphenyl-1-buten-1-yl]phenyl}acrylic acid
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C25H22O2
Molar mass 354.449 g·mol−1
3D model (JSmol)
  • CC/C(=C(\c1ccccc1)/c2ccc(cc2)/C=C/C(=O)O)/c3ccccc3
  • InChI=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-
  • Key: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, [3] [9] [10] of which etacstil is a prodrug (GW-7604 being the 4-hydroxy metabolite of etacstil). [11] This is analogous to the case of tamoxifen being a prodrug of afimoxifene (4-hydroxytamoxifen). [11]

Etacstil was developed in the early 1990s by Duke University, Glaxo Wellcome, and later, Dupont. [12] [13] 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] [9] [12]

After many dormant years, a recent resurgence of interest in SERDs has led to the development of brilanestrant, a structural analogue of etacstil. [9]

See also

Related Research Articles

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<span class="mw-page-title-main">Tamoxifen</span> Medication

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.

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<span class="mw-page-title-main">Toremifene</span> Chemical compound

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<span class="mw-page-title-main">V. Craig Jordan</span> American/British pharmacologist (born 1947)

Virgil Craig Jordan,, is a scientist with American and British citizenship specializing in drugs for breast cancer treatment and prevention. Currently, he is Professor of Breast Medical Oncology, and Professor of Molecular and Cellular Oncology at the University of Texas MD Anderson Cancer Center, Houston, Texas. Previously, he was Scientific Director and Vice Chairman of Oncology at the Lombardi Comprehensive Cancer Center of Georgetown University. Jordan was the first to discover the breast cancer prevention properties of tamoxifen and the scientific principles for adjuvant therapy with antihormones. More recently his work has branched out into the prevention of multiple diseases in women with the discovery of the drug group, selective estrogen receptor modulator (SERMs). Currently, he plans to develop a new Hormone Replacement Therapy (HRT) for post-menopausal women that prevents breast cancer and does not increase the risk of breast cancer.

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<span class="mw-page-title-main">Arzoxifene</span> Chemical compound

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<span class="mw-page-title-main">Brilanestrant</span> Discontinued oral cancer remedy

Brilanestrant (INN) is a nonsteroidal combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was discovered by Aragon Pharmaceuticals and was under development by Genentech for the treatment of locally advanced or metastatic estrogen receptor (ER)-positive breast cancer.

<span class="mw-page-title-main">Elacestrant</span> Chemical compound

Elacestrant, sold under the brand name Orserdu, is an anticancer medication which is used in the treatment of breast cancer. It is taken by mouth.

<span class="mw-page-title-main">Droloxifene</span> Chemical compound

Droloxifene, also known as 3-hydroxytamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was developed originally in Germany and later in Japan for the treatment of breast cancer, osteoporosis in men and postmenopausal women, and cardiovascular disorders but was abandoned and never marketed. It reached phase II and phase III clinical trials for these indications before development was discontinued in 2000. The drug was found to be significantly less effective than tamoxifen in the treatment of breast cancer in two phase III clinical trials.

<span class="mw-page-title-main">Miproxifene</span> Chemical compound

Miproxifene (INN) is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was never marketed. It is a derivative of afimoxifene (4-hydroxytamoxifen) in which an additional 4-isopropyl group is present in the β-phenyl ring. The drug has been found to be 3- to 10-fold more potent than tamoxifen in inhibiting breast cancer cell growth in in vitro models. Miproxifene is the active metabolite of miproxifene phosphate (TAT-59), a phosphate ester and prodrug of miproxifene that was developed to improve its water solubility. Miproxifene phosphate was under development for the treatment of breast cancer and reached phase III clinical trials for this indication but development was discontinued.

<span class="mw-page-title-main">Miproxifene phosphate</span> Chemical compound

Miproxifene phosphate is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was under development in Japan for the treatment of breast cancer but was abandoned and never marketed. It reached phase III clinical trials for this indication before development was discontinued. The drug is a phosphate ester and prodrug of miproxifene (DP-TAT-59) with improved water solubility that was better suited for clinical development. Miproxifene has been found to be 3- to 10-fold as potent as tamoxifen in inhibiting breast cancer cell growth in in vitro models. It is a derivative of afimoxifene (4-hydroxytamoxifen) in which an additional 4-isopropyl group is present in the β-phenyl ring.

<span class="mw-page-title-main">Zindoxifene</span> Chemical compound

Zindoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) that was under development in the 1980s and early 1990s for the treatment of breast cancer but was not marketed. It showed estrogenic-like activity in preclinical studies and failed to demonstrate effectiveness as a treatment for breast cancer in clinical trials. Zindoxifene was the lead compound of the distinct 2-phenylindole class of SERMs, and the marketed SERM bazedoxifene was derived from the major active metabolite of zindoxifene, D-15414. Zindoxifene was first described in 1984.

ZB716, also known as fulvestrant-3-boronic acid, is a synthetic, steroidal, orally active antiestrogen which is under development for the treatment of estrogen receptor (ER)-positive metastatic breast cancer. The drug is a silent antagonist of the ERα (IC50 = 4.1 nM) as well as a selective estrogen receptor degrader (SERD). It is an analogue of fulvestrant in which the C3 hydroxyl group has been replaced with a boronic acid moiety. In accordance, the two drugs have similar pharmacodynamic properties. However, whereas fulvestrant is not orally active and must be administered via intramuscular injection, ZB716 is less susceptible to first-pass metabolism, and in relation to this, is orally active.

<span class="mw-page-title-main">ERX-11</span> Chemical compound

ERX-11, also known as ERα coregulator-binding modulator-11, is a novel antiestrogen and experimental hormonal antineoplastic agent which is being researched for the potential treatment of estrogen receptor-positive breast cancer. It is not a competitive antagonist of the estrogen receptor (ER) like conventional antiestrogens such as tamoxifen or fulvestrant; instead of binding to the ligand-binding site of the ER, ERX-11 interacts with a different part of the ERα and blocks protein–protein interactions of the ERα with coregulators that are necessary for the receptor to act and regulate gene expression. It was designed to bind to the coregulator binding region of the ERα and inhibit the ERα/coactivator interaction, although its precise binding site and mode of action have yet to be fully elucidated and understood. Nonetheless, it is clear that ERX-11 binds within the AF-2 domain of the ERα.

Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.

References

  1. ↑ Kelloff GJ, Hawk ET, Sigman CC (2008-08-17). Cancer Chemoprevention: Volume 2: Strategies for Cancer Chemoprevention. ISBN   9781592597680.
  2. ↑ "GW 5638 Profile". AdisInsight. Springer Nature Switzerland AG.
  3. 1 2 Becnel LB, Darlington YF, Orechsner S, Easton-Marks J, Watkins CA, McOwiti A, et al. "GW 5638". Nuclear Receptor Signaling Atlas. doi:10.1621/B4A9CIQ78V.
  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 (April 2001). "Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor". Cancer Research. 61 (7): 2917–2922. PMID   11306468.
  5. ↑ "GW5638 uniquely alters the shape of the estrogen receptor". The Ben May Department for Cancer Research. The University of Chicago. 2015. Archived from the original on 10 October 2015.
  6. 1 2 "Tamoxifen-like drug suggests new ways to selectively block estrogen". The University of Chicago Medical Center. 12 May 2005. Archived from the original on 2018-03-27. Retrieved 2016-10-25.
  7. ↑ Dardes RC, O'Regan RM, Gajdos C, Robinson SP, Bentrem D, De Los Reyes A, Jordan VC (June 2002). "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. PMID   12060645.
  8. ↑ Tong S, Chen Q, Shan SQ, Dewhirst MW, Yuan F (2006). "Quantitative comparison of the inhibitory effects of GW5638 and tamoxifen on angiogenesis in the cornea pocket assay". Angiogenesis. 9 (2): 53–58. doi:10.1007/s10456-006-9029-x. PMID   16622786. S2CID   35414830.
  9. 1 2 3 Wardell SE, Nelson ER, Chao CA, Alley HM, McDonnell DP (October 2015). "Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader". Endocrine-Related Cancer. 22 (5): 713–724. doi:10.1530/ERC-15-0287. PMC   4545300 . PMID   26162914.
  10. ↑ Bentrem D, Dardes R, Liu H, MacGregor-Schafer J, Zapf J, Jordan V (February 2001). "Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen". Endocrinology. 142 (2): 838–846. doi: 10.1210/endo.142.2.7932 . PMID   11159857.
  11. 1 2 Bentrem D, Dardes R, Liu H, MacGregor-Schafer J, Zapf J, Jordan V (February 2001). "Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen". Endocrinology. 142 (2): 838–846. doi: 10.1210/endo.142.2.7932 . PMID   11159857.
  12. 1 2 "Osteoporosis Drug Bazedoxifene Stops Growth Of Breast Cancer Cells". Medical News Today. 17 June 2013. Archived from the original on 8 January 2014.
  13. ↑ Willson TM, Henke BR, Momtahen TM, Charifson PS, Batchelor KW, Lubahn DB, et al. (May 1994). "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. doi:10.1021/jm00037a002. PMID   8201587.
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