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Selective estrogen receptor degrader

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Aselective estrogen receptor degraderordownregulator (SERD) is a type of drug which binds to the estrogen receptor (ER) and, in the process of doing so, causes the ER to be degraded and thus downregulated.^[1] They are used to treat estrogen receptor-sensitive or progesterone receptor-sensitive breast cancer, along with older classes of drugs like selective estrogen receptor modulators (SERMs) and aromatase inhibitors.^[1]

As of 2016 the only marketed SERD was fulvestrant (brand name Faslodex).^[1] As of November 2016 other SERDs under development include brilanestrant and elacestrant.^[2] 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 large-volume and frequently painful intramuscular injections.^[3] In response, pharmaceutical companies are currently developing oral SERDs. Among products in development are:^[4]

Giredestrant: Roche
Amcenestrant (SAR439859): Sanofi
Camizestrant (AZD9833): AstraZeneca
Rintodestrant (G1T48) : G1 Therapeutics
LSZ102: Novartis
Imlunestrant (LY3484356): Eli Lilly
Elacestrant: Radius
ZN-c5: Zentalis
Taragarestrant (D-0502): Inventisbio
SHR9549: Jiangsu Hengrui
Vepdegestrant (ARV-471): Oral estrogen receptor PROTAC protein degrader for breast cancerbyArvinas.
ZB716 (Fulvestrant boronic acid).
Brilanestrant: Genentech
Etacstil: combined SERM and SERD
[[Palazestrant]]

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).^[5]^[6]^[7]

References[edit]

^ ^a ^b ^c Lee, Clara I; Goodwin, Annabel; Wilcken, Nicholas (3 January 2017). "Fulvestrant for hormone-sensitive metastatic breast cancer". Cochrane Database of Systematic Reviews. 2017 (1): CD011093. doi:10.1002/14651858.CD011093.pub2. PMC 6464820. PMID 28043088.

^ ^a ^b Lai, Ashton C.; Crews, Craig M. (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.

^ "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. Retrieved 2021-01-09.

^ Nalley, Catlin (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, Aditya; Linden, Hannah M.; Ulaner, Gary A.; Chandarlapaty, Sarat; Gosselin, Alice; Celanovic, Marina; Campone, Mario (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.

Estrogens and antiestrogens

Estrogens

ER agonists

Steroidal: Alfatradiol
Certain androgens/anabolic steroids (e.g., testosterone, testosterone esters, methyltestosterone, metandienone, nandrolone esters) (via estrogenic metabolites)
Certain progestins (e.g., norethisterone, noretynodrel, etynodiol diacetate, tibolone)
Clomestrone
Cloxestradiol acetate
Conjugated estriol
Conjugated estrogens
Epiestriol
Epimestrol
Esterified estrogens
Estetrol^†
Estradiol
Estradiol esters (e.g., estradiol acetate, estradiol benzoate, estradiol cypionate, estradiol enanthate, estradiol undecylate, estradiol valerate, polyestradiol phosphate, estradiol ester mixtures (Climacteron))
Estramustine phosphate
Estriol
Estriol esters (e.g., estriol succinate, polyestriol phosphate)
Estrogenic substances
Estrone
Estrone esters
- Estrone sulfate
- Estropipate (piperazine estrone sulfate)
Ethinylestradiol^#
- Ethinylestradiol sulfonate
Hydroxyestrone diacetate
Mestranol
Methylestradiol
Moxestrol
Nilestriol
Prasterone (dehydroepiandrosterone; DHEA)
- Prasterone enanthate
- Prasterone sulfate
Promestriene
Quinestradol
Quinestrol

Progonadotropins

Antiandrogens (e.g., bicalutamide)
GnRH agonists (e.g., GnRH (gonadorelin), leuprorelin)
Gonadotropins (e.g., FSHTooltip follicle-stimulating hormone, LHTooltip luteinizing hormone)

Antiestrogens

ERTooltip Estrogen receptor antagonists (incl. SERMsTooltip selective estrogen receptor modulators/SERDsTooltip selective estrogen receptor downregulators)	Acolbifene^† Anordrin Bazedoxifene Broparestrol Clomifene^# Cyclofenil Enclomifene^† Epitiostanol Lasofoxifene Mepitiostane Ormeloxifene Ospemifene Raloxifene Tamoxifen^# Toremifene Exclusively antagonistic: Elacestrant Fulvestrant Noncompetitive inhibitors: Trilostane
Aromatase inhibitors	First-generation: Aminoglutethimide Testolactone Second-generation: Fadrozole Formestane Third-generation: Anastrozole Exemestane Letrozole
Antigonadotropins	Androgens/anabolic steroids (e.g., testosterone, testosterone esters, nandrolone esters, oxandrolone, fluoxymesterone) D₂ receptor antagonists (prolactin releasers) (e.g., domperidone, metoclopramide, risperidone, haloperidol, chlorpromazine, sulpiride) GnRH agonists (e.g., leuprorelin, goserelin) GnRH antagonists (e.g., cetrorelix, elagolix) Progestogens (e.g., chlormadinone acetate, cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate)
Others	Mixed mechanism of action: Danazol Gestrinone Androstenedione immunogens: Androvax (androstenedione albumin) Ovandrotone albumin (Fecundin)