A novel small molecule targets androgen receptor and its splice variants in castration-resistant prostate cancer

Reactivation of AR appears to be the major mechanism driving the resistance of CRPC to second generation antiandrogens and involves AR overexpression, AR mutation, and/or expression of AR splice variants lacking LBD. There is a need for novel small molecules targeting AR, particularly those also targeting AR splice variants such as ARv7. A high-throughput-high-content screen was previously reported that led to the discovery of a novel lead compound, 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)-1-(4-(2,3-dimethylphenyl)piperazin-1-yl)ethan-1-one (IMTPPE), capable of inhibiting nuclear AR level and activity in CRPC cells, including those resistant to enzalutamide. A novel analog of IMTPPE, JJ-450, has been investigated with evidence for its direct and specific inhibition of AR transcriptional activity via a pulldown assay and RNA-seq analysis, PSA-based luciferase, qPCR, and ChIP assays and xenograft tumor model 22Rv1. JJ-450 blocks AR recruitment to androgen responsive elements (AREs) and suppresses AR target gene expression. JJ-450 also inhibits ARv7 transcriptional activity and its target gene expression. Importantly, JJ-450 suppresses the growth of CRPC tumor xenografts, including ARv7-expressing 22Rv1. Collectively, these findings suggest JJ-450 represents a new class of AR antagonists with therapeutic potential for CRPC, including those resistant to enzalutamide.