发现可选择性降解激动剂结合型雄激素受体（AR ON）的Helicon多肽在前列腺癌中的应用

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 (AR OFF ) 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 AR OFF agents, we developed bifunctional helically-constrained (Helicon) peptide degraders that selectively target the agonist-bound, transcriptionally active conformation of AR (AR ON ). 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 AR OFF agents. These Helicon Allosteric AR ON 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. AR ON 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 AR OFF 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 AR ON 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 AR ON 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 AR ON 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.