Selective estrogen receptor downregulators

A selective estrogen receptor degrader or downregulator (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

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 cancer by Arvinas.
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]

Referencesedit

^ ^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.

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[Cochrane2016-1] 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.

[NRDD2016-2] 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.

[3] "Injection-Site Pain With Large-Volume Intramuscular Injection of Fulvestrant Can Be Minimized". PracticeUpdate. Retrieved 2020-12-28.

[4] "A blockbuster breast cancer niche has Roche and Sanofi in the lead". Evaluate.com. 2020-02-19. Retrieved 2020-12-28.

[5] "Rintodestrant | oral selective estrogen receptor degrader (SERD) | G1 Therapeutics, Inc". www.g1therapeutics.com. Retrieved 2021-01-09.

[6] 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.

[7] 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.

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Investigational

See alsoedit

Referencesedit