Ubiquitination and Degradation in Cancer Therapy

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DESCRIPTION (provided by applicant): Prostate cancer is the most common type of cancer diagnosed in men and the second most common cause of death from cancer. Initial therapy for patients with androgen-dependent prostate cancer includes hormonal therapy to inhibit the biological effects of androgen receptor (AR) signaling. Recent evidence suggests that the AR is critical for tumor growth in androgen-refractory prostate cancer cells. The ubiquitin proteasome pathway is the primary pathway for protein turnover in all eukaryotic cells that involves the assembly of an ubiquitin chain on a substrate, which then targets the multi-ubiquitinated protein for degradation by the 26S proteasome. A protein complex known as, the SCF (Skp1, Cullin, F-box, and Hrtl/Rbx) ubiquitin ligase specifically targets proteins for ubiquitination and subsequent degradation. We previously demonstrated that a bridging molecule or Protac (Proteolysis Targeting Chimeric molecule) promotes in vitro ubiquitination of a stable protein, Methionine Aminopeptidase-2, and an unstable protein, the estrogen receptor, by SCFbeta-TRCP. We have synthesized a Protac (Protac-3) consisting of the ligand of AR, dihydroxytestosterone (DHT), and the kappa(Balpha-phosphopeptide, which binds SCFbeta-TRCP. Our goal is to develop a new technology in which a Protac links the AR to SCFbeta-TRCP, resulting in ubiquitination and degradation of AR. The specific aims of this proposal are to: 1) Test the hypothesis that a phosphopeptide-DHT chimera (Protac-3) will link AR to SCFbeta-TRCP, and direct the ubiquitination and degradation of AR in vitro; 2) Test the hypothesis that a phosphopeptide-DHT chimera (Protac-3) will link AR to SCFbeta-TRCP, and increase the ubiquitination and degradation of AR in cells; and 3) Test the hypothesis that small non-peptidic ligands that bind beta-TRCP can be used to generate testosterone-based Protacs that increase AR ubiquitination and degradation. We hypothesize that AR can be targeted to SCFbeta-TRCP resulting in increased turnover of AR in prostate cancer cells. Development of this technology will lead to novel approaches to treat androgen dependent and -independent disease in hopes of improving the survival of men with prostate cancer.