Drugging the intrinsically disordered transactivation domain of androgen receptor [LNCaP]

Androgen receptor (AR) is a therapuetic target for prostate cancer. Despite therapuetic approaches against its ligand-binding domain (LBD), resistance ultimately develops by mechanisms which result in reactivaton of AR signaling. These mechanisms include expression of constitutively active AR that lacks LBD and fueled the discovery of inhibitors to AR's N-terminal intrinsically disordered transactivation domain (TAD). AR-TAD inhibitors are unique as there is a paucity of small molecule inhibitors that bind directly to intriniscally disordered TADs. Here we reveal gene- and cell specific sensitivities in human prostate cancer cells and xenografts to small molecule inhibitors to AR-TAD. These inhibitors have unique biological functions compared to an AR-LBD inhibitor, including being more efficacious in vivo in a non-castrate setting of androgen-sensitive prostate cancer. These data support a new therapuetic approach for prostate cancer and more broadly reveal the sensitivity of an IDR TAD to small molecule inhibitors on gene expression and cellular pathways. Overall design: To better characterize the molecular differences between AR-TAD inhibitors (ARTADI) EPI-002 and BU3-12 from the AR-LBD inhibitor (enzalutamide), we performed whole genome transcriptional profiling on LNCaP cells in the presence of androgen to specifically look at the effect of each drug on gene expression, and specifically on genes regulated by full length AR. Two control groups (those samples treated with DMSO vehicle in the presence and absence of synthetic androgen R1881) were included to define AR-FL regulated genes. Three biological replicates were included for each group.