Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. We describe a small molecule, SU086, as a therapeutic strategy for advanced prostate cancer. We demonstrate that SU086 inhibits the growth of prostate cancer cells in vitro, cell-line and patient-derived xenografts in vivo, and ex vivo prostate cancer patient specimens. Furthermore, SU086 in combination with standard of care second-generation anti-androgen therapies displays increased impairment of prostate cancer cell and tumor growth in vitro and in vivo. Cellular thermal shift assay reveals that SU086 binds to heat shock protein 90 (HSP90) and leads to a decrease in HSP90 levels. Proteomic profiling demonstrates that SU086 binds to and decreases HSP90. Metabolomic profiling reveals that SU086 leads to perturbation of glycolysis. Our study identifies SU086 as a treatment for advanced prostate cancer as a single agent or when combined with second-generation anti-androgens. Display omitted •SU086 inhibits prostate cancer growth in preclinical models of prostate cancer•SU086 targets heat shock protein 90•SU086 alters prostate cancer glycolysis and decreases intratumoral metabolism•SU086 in combination with anti-androgens halts prostate cancer growth Rice et al. identify SU086 as a therapeutic strategy for treatment of prostate cancer, as it impairs prostate cancer growth, inhibits HSP90, and impairs glycolysis and intratumoral metabolism. SU086 alone and in combination therapy strategies has strong therapeutic potential in pre-clinical models of prostate cancer.