Prostate cancer is the second-leading cause of cancer-related deaths in men worldwide. Whilst first-line hormonal or chemotherapeutic agents show efficacy for the first 1.5–2 years, inevitably the onset of a treatment-resistant and lethal disease variant, castration resistant prostate cancer (CRPC) occurs. A hallmark of CRPC is a marked increase to lipid metabolism. Previous studies have sought to perturb lipid metabolism in CRPC, primarily by targeting the gatekeeper to mitochondrial β-oxidation, CPT-1. However, this approach suffers from severe toxicity as a result of limiting mitochondrial uptake of essential saturated and monounsaturated fatty acids that are critical for normal cellular function. Polyunsaturated fatty acids (PUFAs) on the other hand, play only a minor role in healthy cells but are heavily relied upon in the metabolic environment of CRPC. Unlike other fatty acids, PUFAs require several oxidative steps prior to entering the typical mitochondrial β‑oxidation pathway. The enzyme controlling the rate-limiting step of this auxiliary process is 2,4-dienoyl-CoA reductase (DECR1), which has been shown to be significantly overexpressed in CRPC. Our research team has validated DECR1 as an attractive drug target for CRPC by performing knockdown studies that led to decreased PUFA metabolism and cell death in prostate cancer in vitro and in vivo models.1 A literature search identified the diazaborine family of molecules as potential inhibitors of DECR1, which we further investigated using an in silico screen (unpublished). As such, a comprehensive structure-activity relationship (SAR) study was undertaken by our group on this class of compounds.2 Following from this seminal study, this work aims to further probe the SAR of diazaborines to improve both potency and selectivity as we move towards identifying a lead compound for CRPC treatment.