Helicon Peptides: Degrading Active AR to Overcome Prostate Cancer Resistance

Current AR therapies like enzalutamide target the inactive, unliganded AR conformation (AROFF) by binding its androgen pocket, preventing activation but leaving already active, agonist-bound AR (ARON), the real driver of tumor transcription and proliferation, untouched. This allows resistant tumors to adapt through AR gene amplification, mutations in the ligand-binding domain, or alternative activation pathways, leading to disease progression despite treatment.

Helicon peptide degraders take a radically different approach, selectively recognizing and destroying the the active ARON form. These bifunctional, helically-constrained peptides bind the AF2 coactivator site. By forming high-affinity ternary complexes with E3 ubiquitin ligases (the cell’s cleanup system), they trigger degradation of this proliferative AR pool, directly shutting down genes like KLK3 (PSA) and TMPRSS2 that fuel cancer growth.

Designed via computational de novo modeling and machine learning for cell penetration, these degraders show potent effects in AR-mutant and AR-amplified prostate cancer models. In cell lines, they deliver strong anti-proliferative activity with robust suppression of AR target genes. In vivo, subcutaneous administration in mice is well-tolerated, providing sustained exposure and dose-dependent tumor growth inhibition in the AR-amplified VCaP xenograft model, outperforming standard-of-care enzalutamide, which shows poor efficacy there. Pharmacodynamic markers confirm on-target action: total AR protein and nuclear localization decrease, serum PSA drops markedly, and AR mRNA levels rise due to relief of AR’s auto-repressive negative feedback loop.

Combinations with existing AROFF inhibitors or developmental degraders further boost anti-tumor effects, hitting complementary AR populations, blocking new activation while clearing the active pool already driving resistance. This positions Helicon ARON degraders as a first-in-class strategy with potential to deliver durable responses across androgen-dependent states, including castration-resistant prostate cancer, by overcoming the core limitations of ligand-competitive therapies.

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