Stapled Peptides as Novel Chemical Probes for the Treatment of Castration-Resistant Prostate Cancer

A major unmet medical need in prostate cancer therapy is developing new treatments for castration-resistant prostate cancer (CRPC), an advanced form of prostate cancer associated with poor prognosis and reduced survival. The five-year survival rate for men with distant metastatic prostate cancer is 30%, compared to 100% survival in men with localized prostate cancer. The progression of prostate cancer is driven by the androgen receptor (AR) which consists of three domains [DNA-binding domain (DBD), ligand-binding domain (LBD), transactivation domain (NTD)] and a hinge region. A rapidly emerging mechanism of resistance in CRPC is the development of constitutively active AR splice variants that lack the LBD. This study seeks to diminish AR signaling by targeting the NTD using stapled peptides that inhibit SRC-1, a coactivator of the AR. AR transactivation is controlled mainly by the AF-1 region in the NTD. Solution NMR studies from our collaborators and previously published literature has shown that the Tau1 region in the AR AF-1 interacts with SRC-1. Our hypothesis is that stapled peptides mimicking AR Tau1 will disrupt the interaction between AF-1 and SRC-1. Our research presents the design and synthesis of hydrocarbon stapled peptides and diversity-oriented peptides using solid phase peptide synthesis. We used computational chemistry to improve the design of these peptides by creating a homology model that was used for sequence recovery and alanine scanning experiments. Future studies will characterize the stapled peptides, with the use of our recently developed proteolytic assays, to study their susceptibility to enzymatic degradation, and circular dichroism, to investigate their helicity. Diminished AR signaling through this approach may lead to novel AR-directed therapy for CRPC.