Selective estrogen receptor degrader
A selective estrogen receptor degrader or downregulator (SERD) is a type of drug that selectively binds to the estrogen receptor (ER) and induces its degradation, and thus causes its downregulation.[1] SERDs are used in the treatment of estrogen receptor-positive breast cancer, particularly in cases where tumors have developed resistance to other forms of endocrine therapy, such as selective estrogen receptor modulators (SERMs) or aromatase inhibitors.[1]
The mechanism of action of SERDs involves binding to the estrogen receptor, leading to a conformational change that facilitates recruitment of cellular machinery to degrade the receptor protein. By promoting degradation of the estrogen receptor, SERDs effectively inhibit estrogen signaling within cancer cells, thereby suppressing tumor growth.
A common SERD used in clinical practice is fulvestrant. Fulvestrant is administered as an intramuscular injection and is indicated for the treatment of advanced breast cancer in postmenopausal women whose cancer has progressed following anti-estrogen therapy.
As of 2026 the marketed SERDs are fulvestrant (brand name Faslodex),[1], elacestrant (brand name Orserdu),[2][3] imlunestrant (Inluriyo),[4] and vepdegestrant (Veppanu).[5][6] The clinical success of fulvestrant led to efforts to discover and develop a parallel drug class of selective androgen receptor degraders (SARDs).[2]
Investigational
[edit]Fulvestrant requires intramuscular injections once every two weeks.[7] In response, pharmaceutical companies are currently developing oral SERDs. Among products in development are:[8]
Monofunction (ER ligand) hydrophobic tag degradation:
| Modality | INN | Research Code | Sponsor | Comment |
|---|---|---|---|---|
| Amcenestrant | SAR 439859 | Sanofi | ||
" | Brilanestrant | Genentech | ||
" | Camizestrant | AZD9833 | AstraZeneca | |
" | Elacestrant | Radius | ||
" | Giredestrant | Roche | ||
" | Imlunestrant | LY3484356 | Eli Lilly | |
" | Palazestrant | OP-1250 | Olema Pharmaceuticals | |
" | H3B-6545 | Eisai Co Ltd | SERCA | |
" | ZB716 | EnhancedBio/Zenopharm | Fulvestrant boronic acid | |
carboxylate | Bexirestrant | Menarini | ||
" | Etacstil | GW-5638 | Bristol Myers-Squibb | combined SERM and SERD |
" | Rintodestrant | G1T48 | G1 Therapeutics | |
" | Taragarestrant | D-0502 | Inventisbio | |
" | LSZ102 | Novartis | ||
" | ZN-c5 | Zentalis | ||
? | SHR9549 | Jiangsu Hengrui | ||
| Vepdegestrant | ARV-471 | Arvinas | ||
" | AC 699 | Accutar Biotechnology |
The oral SERDs target ER-positive/HER2-negative breast cancer and are tested as monotherapy and in combination with other drugs such as the CDK inhibitor palbociclib (Ibrance).[9][10][11]
See also
[edit]References
[edit]- 1 2 3 Lee CI, Goodwin A, Wilcken N (January 2017). "Fulvestrant for hormone-sensitive metastatic breast cancer". The Cochrane Database of Systematic Reviews. 1 (1) CD011093. doi:10.1002/14651858.CD011093.pub2. PMC 6464820. PMID 28043088.
- 1 2 Lai AC, Crews CM (February 2017). "Induced protein degradation: an emerging drug discovery paradigm". Nature Reviews. Drug Discovery. 16 (2): 101–114. doi:10.1038/nrd.2016.211. PMC 5684876. PMID 27885283.
- ↑ "FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer". U.S. Food and Drug Administration (FDA). 27 January 2023. Archived from the original on 2 February 2023. Retrieved 1 February 2023.
This article incorporates text from this source, which is in the public domain. - ↑ "Highlights of prescribing information - INLURIYO (imlunestrant) tablets, for oral use" (PDF). Archived from the original (PDF) on 2025-10-29.
- ↑ "Veppanu (vepdegestrant) tablets, for oral use" (PDF). arvinas.com. Retrieved 2026-05-06.
- ↑ "FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer". U.S. Food and Drug Administration (FDA). 1 May 2026. Retrieved 5 May 2026. This article incorporates text from this source, which is in the public domain.
- ↑ "Injection-Site Pain With Large-Volume Intramuscular Injection of Fulvestrant Can Be Minimized". PracticeUpdate. Retrieved 2020-12-28.
- ↑ "A blockbuster breast cancer niche has Roche and Sanofi in the lead". Evaluate.com. 2020-02-19. Retrieved 2020-12-28.
- ↑ "Rintodestrant | oral selective estrogen receptor degrader (SERD) | G1 Therapeutics, Inc". www.g1therapeutics.com. Archived from the original on 2021-01-09. Retrieved 2021-01-09.
- ↑ Nalley C (5 February 2021). "Orally Bioavailable SERD Shows Promise in Certain Breast Cancer Patients". Oncology Times. 43 (3): 35. doi:10.1097/01.COT.0000734348.58210.24.
- ↑ Bardia A, Linden HM, Ulaner GA, Chandarlapaty S, Gosselin A, Celanovic M, et al. (20 May 2019). "Phase 1/2 dose-escalation and expansion study investigating SAR439859 +/- palbociclib in postmenopausal women with estrogen receptor-positive (ER+)/HER2- metastatic breast cancer". Journal of Clinical Oncology. 37 (15_suppl) TPS1105. doi:10.1200/JCO.2019.37.15_suppl.TPS1105. S2CID 190898194.
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