Etacstil

Etacstil
Identifiers
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

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

References

  1. ↑ Cancer Chemoprevention: Volume 2: Strategies for Cancer Chemoprevention.
  2. ↑ "T GW 5638 Profile".
  3. 1 2 "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. 1 2 "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. 1 2 3 "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. 1 2 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. 1 2 "how breast cancer drugs are developed".
  13. ↑ "a non-steroidal estrogen with functional selectivity for bone over uterus in rats.". PMID 8201587.
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