Abstract LB070: Discovery of Helicon peptides that selectively degrade the agonist-bound androgen receptor (ARON) in prostate cancer

Abstract Prostate cancer (PCa) remains largely driven by the androgen receptor (AR) even in castration-resistant settings where AR signaling is maintained through various genetic mechanisms including mutations in the androgen binding pocket and amplifications in the AR locus leading to overexpression of the wild-type protein. Currently approved medicines and investigational molecules in development that block AR signaling or degrade AR necessarily bind to the unliganded conformational state of AR (AROFF) as they bind the androgen binding pocket. This mechanism serves to prevent activation of the protein, rather than targeting it in its active, agonist-bound conformation, which is responsible for driving transcription and tumor cell proliferation. Persistent tumors that retain AR pathway dependence under selective pressure from these agents frequently exhibit adaptive reactivation of AR signaling, which is associated with continued disease progression. To address the limitations of current AROFF agents, we developed bifunctional helically-constrained (Helicon) peptide degraders that selectively target the agonist-bound, transcriptionally active conformation of AR (ARON). Using a combination of computational de novo design and machine learning models for cell penetration, we discovered compounds that bind the AF2 coactivator site, a site distinct from the androgen binding pocket targeted by AROFF agents. These Helicon Allosteric ARON binders were subsequently engineered using ternary complex modeling in concert with medicinal chemistry as E3-specific, proteasome-mediated degraders that exhibit high-affinity binding, potent ternary complex formation and selective degradation of AR. ARON degradation in AR-mutant and AR-amplified prostate cancer cell lines leads to potent anti-proliferative effects along with suppression of transcriptional targets such as KLK3 and TMPRSS2. Notably, combination treatment with standard-of-care AR pathway inhibitors or AROFF degraders in development further improved anti-proliferative effects, supporting a potentially complementary mechanism of action by targeting different pools of AR. Subcutaneous administration of Helicon Allosteric ARON degraders in mice is well tolerated and provides sustained systemic exposure. Treatment leads to potent dose-dependent, durable, and on-target tumor growth inhibition (TGI) in the intact VCaP (AR-amplified) xenograft model with an observed reduction in total AR protein levels and nuclear localization. In contrast, treatment with an AR pathway inhibitor that is current standard-of-care such as enzalutamide exhibits poor tumor growth inhibition in this model. TGI observed with our ARON degraders is also accompanied by a reduction in serum PSA levels and an increase in AR mRNA levels, consistent with relief of AR repression via a negative-feedback loop, a known feature of this model. Together, these data establish selective degradation of the agonist-bound ARON pool as a first-in-class therapeutic strategy with the potential to overcome both mutational and amplification-related limitations of existing AR-directed therapies and deliver durable suppression of AR-driven prostate cancer across androgen states, including castration-resistant disease. Citation Format: Diwakar R. Pattabiraman, Brandon Nicolay, Pieter Beerepoot, Kelsey Barrasso, Dorothy Brach, Sascha DeVine, Lee Belding, Paula Ortet, Anthony Quartararo, Archana Iyer, Yelena Arnautova, David Terry, Dakota Hawkins, Shelagh Fluharty, Amelia K. Luciano, Brandon Hriniak, Mousa Jafari, Anandan Palani, Donovan Chin, Markus Haeberlein, Jonathan Hurov. Discovery of Helicon peptides that selectively degrade the agonist-bound androgen receptor (ARON) in prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB070.