Developing isoform-selective Hsp90 inhibitors for monotherapy and enhanced immunotherapy against lethal prostate cancer

PROJECT SUMMARY/ABSTRACT This project focuses on pioneering a novel approach in anti-cancer drug development through the creation and optimization of isoform-selective inhibitors targeting the 90 kDa heat shock protein (Hsp90β). Hsp90 is a crucial chaperone protein involved in the maturation of over 400 client proteins, many of which play significant roles in cancer progression. The selective inhibition of Hsp90β over other isoforms offers a promising strategy to mitigate the side effects associated with pan-Hsp90 inhibitors, such as ocular, cardio, and dose-escalating toxicities, which have hindered the clinical success of these treatments. The objectives of this research include the development of Hsp90β-selective inhibitors that demonstrate high affinity and selectivity, without inducing the heat shock response (HSR) or causing toxicity, thereby overcoming major challenges faced in clinical trials of pan-Hsp90 inhibitors. Preliminary data indicate these inhibitors not only reduce the proliferation of prostate cancer cell lines but also enhance the efficacy of immune checkpoint blockade (ICB) therapy in prostate cancer models, suggesting their potential to transform treatment- resistant cancers into manageable diseases. Novel Hsp90β-inhibitors with improved solubility were created and will be tested in the current study. The specific aims of the project are threefold: 1. To enhance the pharmacological properties of Hsp90β-selective inhibitors for effective in vivo use against cancer, focusing on solubility, permeability, and half-life while preserving specificity. 2. To evaluate the impact of Hsp90β-inhibitors on client protein profiles in comparison with non-selective Hsp90 inhibitors, aiming to elucidate mechanisms of action and identify biomarkers for efficacy and resistance. 3. To assess the efficacy and safety of Hsp90β-inhibitors in primary and metastatic castration-resistant prostate cancer (CRPC) models, examining their potential to synergize with ICB therapy and improve immunotherapy outcomes. This research aligns with the National Institutes of Health's mission to advance science and applications that improve health outcomes. By focusing on the development of selective drug candidates, this project aims to offer new therapeutic options for metastatic CRPC and potentially other cancers, addressing a significant unmet need in oncology. The outcomes of this study are expected to pave the way for clinical trials, contributing to the broader goal of enhancing cancer treatment strategies and patient survival rates.