Etacstil

Etacstil

Identifiers
IUPAC name (2E)-3-{4-[(1Z)-1,2-Diphenyl-1-buten-1-yl]phenyl}acrylic acid
CAS Number	155701-61-4
PubChem (CID)	5288494
ChemSpider	4450668
ChEMBL	CHEMBL33899
Chemical and physical data
Formula	C25H22O2
Molar mass	354.45 g·mol^−1
3D model (Jmol)	Interactive image
SMILES CC/C(=C(\c1ccccc1)/c2ccc(cc2)/C=C/C(=O)O)/c3ccccc3
InChI 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, non-steroidal, 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

• Bazedoxifene
• Elacestrant
• Timeline of cancer treatment development

References

1. Cancer Chemoprevention: Volume 2: Strategies for Cancer Chemoprevention.
2. "T GW 5638 Profile".
3. "Nuclear Receptor Signaling Atlas.".
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."Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational change in the estrogen receptor.". Cancer Res. 2001. PMID 11306468.
5. "GW5638 uniquely alters the shape of the estrogen receptor .".
6. "Tamoxifen-like drug suggests new ways to selectively block estrogen.".
7. "Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo.". Clin Cancer Res. 2002. PMID 12060645.
8. "Quantitative comparison of the inhibitory effects of GW5638 and tamoxifen on angiogenesis in the cornea pocket assay.". Angiogenesis. 2006. doi:10.1007/s10456-006-9029-x.
9. "Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader.".
10. "Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen.". PMID 11159857.
11. Bentrem D, Dardes R, Liu H, MacGregor-Schafer J, Zapf J, Jordan V (2001). "Molecular mechanism of action at estrogen receptor alpha of a new clinically relevant antiestrogen (GW7604) related to tamoxifen". Endocrinology. 142 (2): 838–46. doi:10.1210/endo.142.2.7932. PMID 11159857.
12. "how breast cancer drugs are developed".
13. "a non-steroidal estrogen with functional selectivity for bone over uterus in rats.". PMID 8201587.