Rational design, synthesis, and biological evaluation of Raloxifene-based potent degrader of estrogen receptor alpha

In this study, we rationally optimized the benzothiophene scaffold of the SERM raloxifene through strategic linker modifications, culminating in the discovery of B7, a potent ERα Degrader validated by structure-activity relationship analysis. At the cellular level, B7 demonstrated enhanced anti-proliferative activity against ERα-positive breast Cancer models, with IC₅₀ values of 3.39 μM (MCF-7) and 0.68 μM (T47D). Western blot analysis confirmed B7's capacity to effectively degrade ERα protein in both cell lines. Flow cytometry revealed that B7 induces G0/G1 phase arrest in MCF-7 cells, elucidating its primary anti-proliferative mechanism. Furthermore, B7 significantly inhibited MCF-7 cell migration in wound-healing assays. Pharmacokinetic studies indicated limited oral bioavailability (7.5 %) in rat models. Molecular docking confirmed B7's high ERα affinity, with key interactions stabilizing the ligand-receptor complex. In the T47D xenograft mouse model, the combination of B7 and Palbociclib demonstrated potent antitumor activity, achieving a tumor growth inhibition rate of 89.2 %. Further structural modification based on B7 may lead to the development of a candidate.

Antitumor; Biological evaluation; Degrader; ERα; Molecular; Rational design.