Selective estrogen receptor degrader, SERD (3)
A Study Evaluating the Efficacy and Safety of GDC-9545 Combined With Palbociclib Compared With Letrozole Combined With Palbociclib in Participants With Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer
A Study Evaluating the Efficacy, Safety, and Pharmacokinetics of GDC-9545 Plus Palbociclib Compared With Anastrozole Plus Palbociclib for Postmenopausal Women With Estrogen Receptor-Positive and HER2-Negative Untreated Early Breast Cancer
A Study of GDC-9545 Alone or in Combination With Palbociclib and/or Luteinizing Hormone-Releasing Hormone (LHRH) Agonist in Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer
A Study of GDC-9545 in Postmenopausal Women With Stage I-III Operable, Estrogen Receptor-Positive Breast Cancer
This compound and its use are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.
A novel selective estrogen receptor degrader (SERD) (GDC-9545)
The estrogen receptor (ER)
The ER is a ligand-sensitive transcription factor expressed in various tissues, including the breast, where it can drive ER+ tumor cell division.1
The ER signaling pathway
The activating ligand estrogen enters the cell and binds to the ligand-binding domain of the ER, promoting the dynamic association of the ER with specific regions of DNA.1 Hotspot mutations in the ER (eg, Y537S and D538G) allow for estrogen-independent activation of the ER.2-4
The activated ER triggers the expression of numerous target genes, including cyclin D1 (CCND1), which regulates the activity of cyclin-dependent kinases 4 and 6 (CDK4/6), and the progesterone receptor (PGR).5,6
The gene expression program activated by the ER promotes ER+ tumor growth by driving cell proliferation.1
GDC-9545 is an investigational molecule designed to inhibit the ER
GDC-9545, an investigational small molecule, is a full ER antagonist belonging to the SERD class of therapeutics.7,8
GDC-9545 targets ER-induced tumor proliferation
Preclinical studies suggest that GDC-9545 is orally bioavailable and competitively inhibits the binding of estrogen to the ER.7,9
In preclinical models, GDC-9545 has been shown to restrain the normally dynamic behavior of both wild-type and mutant ER, immobilizing the ER and attenuating the expression of its target genes.7,9,10 The ER is subsequently degraded by the proteasome, which may lead to a reduction in ER protein level without completely eliminating it.7,9
In preclinical models, GDC-9545 demonstrates inhibition of the ER-induced proliferative program and suppression of tumor growth.7,9
As with other SERDs, the addition of CDK4/6 inhibitors may potentially enhance the antiproliferative effect of GDC-9545 in ER+ breast cancer cells.11
- Liang J, Shang Y. Estrogen and cancer. Annu Rev Physiol. 2013;75:225-240.
- Metcalfe C, Friedman LS, Hager JH. Hormone-targeted therapy and resistance. Annu. Rev. Cancer Biol. 2018;2:291-312.
- Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45(12):1439-1445.
- Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45(12):1446-1451.
- O'Lone R, Frith MC, Karlsson EK, Hansen U. Genomic targets of nuclear estrogen receptors. Mol Endocrinol. 2004;18(8):1859-1875.
- Kim JK, Diehl JA. Nuclear cyclin D1: an oncogenic driver in human cancer. J Cell Physiol. 2009;220(2):292-296.
- Metcalfe C, Ingalla E, Blake RA, et al. Poster presented at the 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. Abstract P5-04-07.
- Jhaveri K, Winer EP, Lim E, et al. Poster presented at the 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. Abstract PD7-05.
- Wang X. Presented at 2020 American Association for Cancer Research Virtual Annual Meeting I; April 22-27, 2020. Abstract DDT02-05.
- Guan J, Zhou W, Hafner M, et al. Therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell. 2019;178(4):949-963.e18.
- Iorfida M, Mazza M, Munzone E. Fulvestrant in combination with CDK4/6 inhibitors for HER2- metastatic breast cancers: current perspectives. Breast Cancer (Dove Med Press). 2020;12:45-56.