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.{{cite journal | vauthors = Lee CI, Goodwin A, Wilcken N | title = Fulvestrant for hormone-sensitive metastatic breast cancer | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD011093 | date = January 2017 | pmid = 28043088 | pmc = 6464820 | doi = 10.1002/14651858.CD011093.pub2 }} 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.

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 2016 the only marketed SERD was fulvestrant (brand name Faslodex). As of November 2016 other SERDs under development include brilanestrant and elacestrant.{{cite journal | vauthors = Lai AC, Crews CM | title = Induced protein degradation: an emerging drug discovery paradigm | journal = Nature Reviews. Drug Discovery | volume = 16 | issue = 2 | pages = 101–114 | date = February 2017 | pmid = 27885283 | pmc = 5684876 | doi = 10.1038/nrd.2016.211 }} The clinical success of fulvestrant led to efforts to discover and develop a parallel drug class of selective androgen receptor degraders (SARDs).

Investigational

{{See also|List of investigational sex-hormonal agents#Estrogenics}}

Fulvestrant requires intramuscular injections once every two weeks.{{Cite web|title=Injection-Site Pain With Large-Volume Intramuscular Injection of Fulvestrant Can Be Minimized|url=https://www.practiceupdate.com/content/injection-site-pain-with-large-volume-intramuscular-injection-of-fulvestrant-can-be-minimized/52698|access-date=2020-12-28|website=PracticeUpdate|language=en}} In response, pharmaceutical companies are currently developing oral SERDs. Among products in development are:{{Cite web|date=2020-02-19|title=A blockbuster breast cancer niche has Roche and Sanofi in the lead|url=https://www.evaluate.com/vantage/articles/news/corporate-strategy/blockbuster-breast-cancer-niche-has-roche-and-sanofi-lead|access-date=2020-12-28|website=Evaluate.com|language=en}}

Monofunction (ER ligand) hydrophobic tag degradation:

Modality	INN	Research Code	Sponsor	Comment
class="wikitable" \|+ List of Selective Estrogen Receptor Degraders (SERDs)
{{Center\|hydrophobic tag}}	Amcenestrant	SAR 439859	Sanofi
{{Center\|"}}	Brilanestrant		Genentech
{{Center\|"}}	Camizestrant	AZD9833	AstraZeneca
{{Center\|"}}	Elacestrant		Radius
{{Center\|"}}	Giredestrant		Roche
{{Center\|"}}	Imlunestrant	LY3484356	Eli Lilly
{{Center\|"}}	Palazestrant	OP-1250	Olema Pharmaceuticals
{{Center\|"}}		H3B-6545	Eisai Co Ltd	SERCA
{{Center\|"}}		ZB716	EnhancedBio/Zenopharm	Fulvestrant boronic acid
{{Center\|carboxylate}}	Bexirestrant		Menarini
{{Center\|"}}	Etacstil	GW-5638	Bristol Myers-Squibb	combined SERM and SERD
{{Center\|"}}	Rintodestrant	G1T48	G1 Therapeutics
{{Center\|"}}	Taragarestrant	D-0502	Inventisbio
{{Center\|"}}		LSZ102	Novartis
{{Center\|"}}		ZN-c5	Zentalis
{{Center\|?}}		SHR9549	Jiangsu Hengrui
{{Center\|PROTAC}}	Vepdegestrant	ARV-471	Arvinas
{{Center\|"}}		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).{{Cite web|title=Rintodestrant {{!}} oral selective estrogen receptor degrader (SERD) {{!}} G1 Therapeutics, Inc.|url=https://www.g1therapeutics.com/pipeline/rintodestrant/|access-date=2021-01-09|website=www.g1therapeutics.com}}{{cite journal | vauthors = Nalley C |title=Orally Bioavailable SERD Shows Promise in Certain Breast Cancer Patients |journal=Oncology Times |date=5 February 2021 |volume=43 |issue=3 |pages=35 |doi=10.1097/01.COT.0000734348.58210.24 }}{{cite journal | vauthors = Bardia A, Linden HM, Ulaner GA, Chandarlapaty S, Gosselin A, Celanovic M, Campone M |title=Phase 1/2 dose-escalation and expansion study investigating SAR439859 +/- palbociclib in postmenopausal women with estrogen receptor-positive (ER+)/HER2- metastatic breast cancer |journal=Journal of Clinical Oncology |date=20 May 2019 |volume=37 |issue=15_suppl |pages=TPS1105 |doi=10.1200/JCO.2019.37.15_suppl.TPS1105 |s2cid=190898194 }}

References

Category:Antiestrogens

Category:Hormonal antineoplastic drugs