A small molecule BAG1 inhibitor as therapeutic agent for androgen receptor positive prostate cancer

BAG1 is a family of polypeptides with a conserved C-terminal BAG domain that functions as a nucleotide exchange factor for the molecular chaperone HSP70. BAG1 proteins also bind to diverse cellular proteins and control several signaling processes including proteostasis, apoptosis and transcription. The largest BAG1 isoform (BAG1L) controls the activity of the androgen receptor and is upregulated in prostate cancer. Here, we show that BAG1L binds to the AR N-terminal domain (NTD) and regulates AR dynamics and the expression of AR target genes. We further show that disruption of the BAG1L-AR NTD action by targeting the BAG domain with a small molecule, 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17), downregulates AR target gene expression and blocks proliferation of AR-positive prostate cancer cells. A4B17 also inhibits tumor development in mouse xenograft models under castration conditions. A4B17 is therefore a BAG1 inhibitor with unique properties to inhibit prostate cancer growth. Overall design: LAPC-4 cells were treated with vehicle, A4B17 and enzalutamide