Giredestrant is an oral selective estrogen receptor (ER) degrader. Giredestrant can induce an inactive conformation of the estrogen receptor ligand binding domain and promoting proteasome-mediated degradation of the receptor protein. Giredestrant is used to treat estrogen receptor-positive (ER+) breast cancer [1-5].
Giredestrant significantly degraded ERα protein and inhibited proliferation at low nanomolar concentrations (0.1nM, 1nM, 10nM, 100nM and 1μM, 24h) in a variety of ER+ breast cancer cell lines (MCF-7, T-47D, CAMA-1 and HCC1500) [5]. In T47D cells, treatment with Giredestrant (50nM, 6d) reduced T47D cell viability [6].
In the HCI-013PDX animal model, Giredestrant (1mg/kg, po, 29d) can strongly induce tumor regression, showing excellent anti-tumor potential [5]. In the HCI-013 PDX model, Giredestrant (30mg/kg, po, 28d) suppressed the mutant ERα-PR proliferation in the mammary gland more so than the standard-of-care agents, tamoxifen and fulvestrant [7]. In the transgenic Esr1 animal model, Giredestrant (30mg/kg, po, 4d) exhibited an antiproliferative response against ESR1 mutant tumors [8].
References:
[1]. Malhi V, Agarwal P, Gates MR, et al. Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer. Cancer Research Communications. 2023 Dec 15; 3(12): 2551-2559.
[2]. Martín M, Lim E, Chavez-MacGregor M, et al. Giredestrant for estrogen receptor–positive, HER2-negative, previously treated advanced breast cancer: Results from the randomized, phase II acelERA breast cancer study. Journal of Clinical Oncology. 2024 Jun 20; 42(18): 2149-2160.
[3]. Jhaveri KL, Bellet M, Turner NC, et al. Phase Ia/b study of giredestrant±palbociclib and±luteinizing hormone-releasing hormone agonists in estrogen receptor–positive, HER2-negative, locally advanced/metastatic breast cancer. Clinical Cancer Research. 2024 Feb 16; 30(4): 754-766.
[4]. Pathak N, Oliveira M. New Oral Selective Estrogen Receptor Degraders Redefine Management of Estrogen Receptor–Positive Breast Cancer. Annual Review of Medicine. 2025 Jan 27; 76(1): 243-255.
[5]. Liang J, Zbieg JR, Blake RA, et al. GDC-9545 (Giredestrant): a potent and orally bioavailable selective estrogen receptor antagonist and degrader with an exceptional preclinical profile for ER+ breast cancer. Journal of Medicinal Chemistry. 2021 Jul 12; 64(16): 11841-11846.
[6]. Herrera-Abreu MT, Guan J, Khalid U, et al. Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer. Nature Communications. 2024 Nov 5; 15(1): 9550.
[7]. Liang J, Ingalla ER, Yao X, et al. Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor mutations in breast cancer. Science Translational Medicine. 2022 Sep 21; 14(663): eabo5959.
[8]. Liang J, Yao X, Aouad P, et al. ERα dysfunction caused by ESR1 mutations and therapeutic pressure promotes lineage plasticity in ER+ breast cancer. Nature Cancer. 2025 Jan 13: 1-5.
Giredestrant是一种口服选择性雌激素（ER）受体降解剂。Giredestrant可以诱导雌激素受体配体结合域失活构象，并促进蛋白酶体介导的受体蛋白降解。Giredestrant用于治疗雌激素受体阳性(ER+)乳腺癌 [1-5]。
Giredestrant在低纳摩尔浓度（0.1nM、1nM、10nM、100nM和1μM，24h）下，显著降解ERα蛋白，并抑制多种ER+乳腺癌细胞系（MCF-7、T-47D、CAMA-1 和 HCC1500）的增殖 [5]。在T47D细胞中，用Giredestrant（50nM，6d）治疗可使T47D细胞活力降低 [6]。
在HCI-013PDX动物模型中，Giredestrant（1mg/kg，po，29d）可强烈诱导肿瘤消退，显示出优异的抗肿瘤潜力 [5]。在HCI-013PDX模型中，Giredestrant（30mg/kg，po，28d）对乳腺中突变型ERα-PR增殖的抑制作用优于标准治疗药物他莫昔芬和氟维司群 [7]。在转基因Esr1动物模型中，Giredestrant（30mg/kg，po，4d）表现出对ESR1突变型肿瘤的抗增殖作用 [8]。