Abstract 2281: AZD4241, an orally bioavailable ERα PROTAC, degrades wild-type and mutant ERα and delivers anti-tumour activity in preclinical breast cancer models

Abstract Estrogen receptor alpha (ERα) is a member of the nuclear hormone receptor superfamily and a key driver of hormone receptor-positive (HR+) breast cancer. Current ER-pathway inhibitors include aromatase inhibitors (letrozole, anastrozole, exemestane), selective estrogen receptor modulators (SERMs; tamoxifen), and selective estrogen receptor degraders (SERDs; fulvestrant, elacestrant, imlunestrant). In metastatic ER-positive disease, resistance is common and often involves the emergence of ESR1 mutations (e.g., Y537S, D538G). These mutations occur in the ligand-binding domain of ERα and enable ligand-independent ER activation, reducing the effectiveness of aromatase inhibitors and some antagonists. This underscores the need for novel treatments that target ER in both wild-type (ESR1wt) and mutant (ESR1m) settings, including more effective ERα degraders, as demonstrated clinically by SERDs. Here we characterise AZD4241, a novel ER-targeting proteolysis targeting chimera (PROTAC), that degrades both wt and mutant ERα and delivers anti-tumour efficacy in preclinical breast cancer models. AZD4241 degraded ERα in ESR1wt cell lines (IC50 0.4 nM in MCF7 cells) and showed good oral bioavailability across species. ERα half-life was reduced through PROTAC-mediated degradation requiring cereblon engagement and proteasomal activity. In MCF7 cells engineered to express clinically relevant ESR1 mutations, AZD4241 reduced ERα with degradation potency (IC50 0.2-1.0 nM) comparable to ESR1wt controls. AZD4241 completely inhibited estradiol-induced gene expression (e.g., GREB1, PGR, and TFF1) and suppressed proliferation of ER-dependent breast cancer cell lines with low-nanomolar IC50 values. In vivo, AZD4241 induced dose-dependent anti-tumour activity and, in some cases, tumour regressions across ESR1wt and ESR1m patient-derived xenograft (PDX) models, including a palbociclib-resistant model. Efficacy was associated with marked reductions in ERα protein levels and decreased ER pathway activity, supporting a pharmacodynamic link between target degradation, suppression of ER signalling and efficacy. Collectively, these data confirm that AZD4241 is a potent, orally bioavailable degrader of wt and mutant ERα, driving anti-tumour efficacy in ESR1wt, ESR1m, and CDK4/6 inhibitor-resistant PDX models. These findings support the use of AZD4241 as a novel ER-PROTAC with potential to overcome key resistance mechanisms to current standards of care and deliver clinical benefit for patients with ER-positive breast cancer. Citation Format: Mandy Lawson, Natalie Cureton, Lynet Nyoni, Sophie D’Arcy, Lydia Parkinson, Ana Quiroga, Pablo Morentin Gutierrez, Ji Li, Hana Baakza, Thomas Hayhow, Claire Crafter, Lucy Ireland, Gemma Hardman Fowler, Georgia M. Simmons, Lakjaya Buluwela, Simak Ali, Neil Gibson. AZD4241, an orally bioavailable ERα PROTAC, degrades wild-type and mutant ERα and delivers anti-tumour activity in preclinical breast cancer models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2281.