AZD4241：一种口服生物利用度良好的ERalpha PROTAC，可降解野生型和突变型ERalpha并在临床前乳腺癌模型中发挥抗肿瘤活性

Estrogen receptor alpha (ERalpha) 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 ERalpha 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 ERalpha degraders, as demonstrated clinically by SERDs. Here we characterise AZD4241, a novel ER‑targeting proteolysis targeting chimera (PROTAC), that degrades both wt and mutant ERalpha and delivers anti‑tumour efficacy in preclinical breast cancer models. AZD4241 degraded ERalpha in ESR1wt cell lines (IC 50 0.4 nM in MCF7 cells) and showed good oral bioavailability across species. ERalpha 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 ERalpha with degradation potency (IC 50 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 IC 50 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 ERalpha 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 ERalpha, 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.