Palazestrant在体外直接募集辅阻遏蛋白NCoR1，从而完全拮抗雌激素受体alpha

The estrogen receptor (ER) is a well-established driver of breast cancer with approximately 80% of patients presenting as ER-positive (ER+). The current treatment paradigm relies on endocrine therapies; however, there are pharmacokinetic, efficacy and tolerability issues with approved agents indicating a clear unmet need for better treatments for patients. Palazestrant, a complete estrogen receptor antagonist (CERAN), has demonstrated favorable tolerability and efficacy in a heavily pre-treated patient population and is currently being evaluated in two Phase III clinical trials (OPERA-01 and OPERA-02) for the treatment of ER+/HER2-metastatic breast cancer. We previously described preclinical characterization of this molecule (Parisan et al., 2023; Ng et al., 2025) where we demonstrated that palazestrant is a novel, orally bioavailable complete ER antagonist and selective ER degrader that completely blocks estrogen-induced transcriptional activity and demonstrates impressive in vitro and in vivo antitumor activity. As a CERAN, palazestrant can inactivate both the AF-2 and AF-1 domains of ER-alpha resulting in complete antagonism that does not demonstrate any agonist activity. Here we show for the first time that palazestrant and other CERANs completely and potently recruit the corepressor protein NCoR1 to ERalpha as part of their mechanism of action. Contrarily, selective estrogen receptor modulators (SERMs) such as 4-OH-tamoxifen and vepdegestrant either do not induce recruitment or are incomplete recruiters, in line with previous data indicating that SERMs are not complete antagonists. At the transcriptional level, palazestrant more potently suppresses the transcription of key E2 and cell cycle related genes such as PGR and GREB1 in ER+ breast cancer models as compared to 4-OH-tamoxifen, with strong downregulation observed at concentrations of 5 nM and lower. CERAN molecules palazestrant and fulvestrant consistently demonstrate greater suppression of GREB1 and PGR as compared to SERMs in both ESR1 wildtype and mutant ER+ breast cancer models.Functionally, treatment with palazestrant leads to antiproliferative activity in ER+ breast cancer models comparable or superior to investigational and approved anti-estrogens. All molecules that demonstrate complete antagonism of ER demonstrate a greater total inhibition of proliferation (Emax %). Importantly, in the CAMA-1 ER+/HER2 model, palazestrant demonstrates a complete suppression of cell proliferation where tamoxifen does not. When cells are not stimulated with E2, SERMs like tamoxifen demonstrate induction of cell proliferation where CERANs do not. Palazestrant is a promising therapeutic strategy for treating ER+/HER2- breast cancer patients and is being evaluated clinically, both as monotherapy and combination.