PROJECT SUMMARY The overarching goal of this application is to develop a small molecule(s) that targets both the AR and epigenetic dysfunction for the treatment of castration-resistant prostate cancer (CRPC). Uncontrolled activation of androgen receptor (AR) is responsible for the development and progression of prostate cancer (PCa). Similarly, epigenetic events mediated through histone-modifying enzymes, such as histone deacetylases (HDACs), are essential to the regulation of AR signaling. Inhibition of HDACs suppress PCa cell proliferation through multiple mechanisms including AR degradation that results in the inhibition of AR signaling. Although, the current AR inhibitors (enzalutamide and abiraterone) are initially effective, these treatments eventually fail because of factors such as, AR-splice variants (AR-SVs) and AR responding to stimuli other than androgen. Systemic HDAC inhibitors (HDACi), despite promising preclinical efficacy, have shown sub-optimal effects in clinical studies of patients with CRPC. An effective way to control the emergence and treatment of CRPC is to develop small molecules that employ multiple mechanisms to 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. The hypothesis is that rationally designed antiandrogen- equipped HDACi with enhanced bioavailability and potency will constitute a new generation of novel, targeted anti-PCa agents that will effectively inhibit the growth of both AR+ and AR-SV early stage PCa and CRPC by directly targeting AR through its degradation. The preliminary studies have furnished lead compounds (antiandrogen-HDACi) which engage with AR for selective tumor/tissue distribution, and potently inhibit AR, HDACs 1 and 6 for therapeutic impact. The proposed research will solve two problems of main-stream cancer therapy agents – resistance development of antiandrogens and lack of solid tumor efficacy of HDACi – to furnish a novel class of targeted agents with potential to positively impact CRPC treatment. The specific aims are: 1) Identify antiandrogen-HDACi with optimized pharmacokinetic (PK) properties and clean toxicity profile. 2) Investigate the mechanism of action and characterize the correlation between intracellular HDAC and AR inhibition in the promising antiandrogen-HDACi. 3) Determine the therapeutic efficacy of the promising antiandrogen-HDACi to inhibit CRPC growth in patient’s derived xenograft (PDX) and orthotopic implantation models via oral administration.