Friday, April 19, 2024
4/19/2024
Project Summary/Abstract Current AR inhibitors (enzalutamide and abiraterone) inhibit either the conversion of androgen to dihydrotestosterone (DHT), block androgen binding to androgen receptor (AR), or AR signaling. Although initially effective, these treatments eventually fail because of factors such as, AR-splice variants (AR-SVs) and AR responding to stimuli other than androgen. An effective way to control the emergence and treatment of castration-resistant prostate cancer (CRPC) is to develop small molecules that either inhibit AR expression or promote its degradation. If there is no AR, there would be no AR signaling, regardless of whether or how much androgen or other stimuli of AR signaling are present in CRPC. Our preliminary studies demonstrated that naturally occurring Urolithin A (UroA) inhibited the AR signaling and selectively suppressed the growth of AR-positive (AR+: IC50 ~35 ¿M) but not AR-negative (AR-: IC50 ~70 µM) CRPC in both in vitro and in vivo models (50 mg/kg/body weight). As higher concentrations of UroA are required to suppress CRPC growth, we aimed to design and develop potent UroA analogs that could selectively inhibit AR activation at lower concentrations (nM), are orally bioavailable and suppress the growth of CRPC. The subsequent development of a series of UroA analogs and structure-activity relationship (SAR) studies led to the identification of two novel lead compounds ASR-600 and ASR-603 (US Provisional 62/941588) which demonstrated better efficacy (nM) than UroA (ASR-600: >40-fold and ASR-603: >12-fold) in inhibiting AR signaling in CRPC cell lines. Molecular studies suggest these two ASRs inhibit both AR and AR-SVs expression via ubiquitination and degradation within the cytosol. Molecular dynamic (MD) system simulation studies, biophysical analysis based on nuclear magnetic resonance (NMR), and thermal shift assays showed that these small molecules bind to the N-terminal domain (NTD) of AR and block the activation of both AR and AR-SV. At physiologically achievable concentrations, ASR-600 abrogated AR+ and AR-SV (C4-2B and 22Rv1) tumor growth in xenografts. Based on our preliminary results, we hypothesized that ‘Rationally designed ASRs will effectively inhibit and/or promote the degradation of both AR and AR-SV expression by directly targeting the AR-NTD and inhibit the growth of CRPC. We will test this hypothesis with the following specific aims. Aim 1. Investigate the mechanism of action of ASRs on AR+ CRPC cells. Aim 2. Determine in vivo signaling mechanism of AR and AR-SVs expression and optimize the dose of ASRs. Aim 3. Determine the therapeutic efficacy of the ASRs to inhibit CRPC growth in orthotopic and patient-derived xenograft (PDX) models. The proposed studies will elucidate the mechanism of action of the ASRs and lead to a better understanding of the chemotherapeutic properties of these compounds against CRPC.
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