GSK5471713：一种新型、选择性口服雄激素受体降解剂，具有同类最佳（best-in-class）潜力用于治疗前列腺癌

The a ndrogen r eceptor (AR) is a ligand-dependent transcription factor that controls expression of genes involved in normal prostate development and is a critical driver of prostate cancer growth and survival. Patients with locally advanced or metastatic disease are frequently treated with AR p athway i nhibitors (ARPIs) targeting AR (e.g., enzalutamide) and/or androgen synthesis (e.g., abiraterone), and while these therapies offer survival benefit, patients frequently develop resistance via reactivation of AR signaling. AR pathway re-activation is often mediated by direct alterations to AR, including gene amplification, structural rearrangements, point mutations in the l igand b inding d omain (LBD), and co-expression of constitutively active splice variants. In total, AR alterations are observed in >60% of m etastatic c astration r esistant p rostate c ancer (mCRPC) patients and are associated with resistance to ARPIs. Heterobifunctional degraders recruit proteins of interest to the ubiquitin-proteasome system for targeted degradation. As these molecules degrade their target protein, they offer an opportunity to overcome or avoid resistance mechanisms impacting inhibitors of functional activity. We disclose herein GSK5471713 as a potent and selective oral AR degrader, comprised of an AR LBD ligand linked to a binder of the E3 ubiquitin ligase CRBN. GSK5471713 potently degrades all clinically relevant forms of full-length AR, including wild type, LBD mutants, and in amplified settings. Similar to other AR degraders currently in clinical development, it functions as a dual AR degrader and antagonist. GSK5471713 potently degrades full-length AR in prostate cancer cell lines in vitro , resulting in transcriptional down-regulation of AR-dependent genes and gene signatures and inhibition of cell growth. Increased potency is observed for GSK5471713 in prostate cancer cell lines in vitro compared to both enzalutamide and other AR degraders. In vivo , GSK5471713 induces time- and dose-dependent AR degradation in prostate cancer xenografts. Daily oral administration induces dose-dependent tumor growth inhibition and tumor regressions, with commensurate decreases in plasma PSA levels. Comparison of the in vivo activity of GSK5471713 to enzalutamide and other AR degraders dosed at clinical exposure equivalents suggest an opportunity for differentiated efficacy. In total, these data demonstrate GSK5471713 as a potential best-in-class AR degrader offering benefit to patients with prostate cancer. GSK5471713 is expected to advance into Phase 1 clinical studies in early 2026.