Transcriptional profiles of castration resistant prostate cancer cells treated with ITRI-148 PROTAC targeting AR and AR-V7
Androgen receptor (AR) signaling remains a key driver of castration-resistant prostate cancer, with AR splice variants like AR-V7 mediating resistance to second-generation antiandrogens. Targeting the AR N-terminal domain (NTD) offers a strategy to bypass ligand-binding domain-mediated resistance. We developed a VHL-based (ITRI-90) and a CRBN-based (ITRI-148) PROTAC degrader capable of targeting AR and AR-V7 via NTD. These compounds demonstrate potent antitumor activity towards castration-resistant and enzalutamide resistant xenograft models. Transcriptomic analyses confirm robust suppression of AR and AR-V7 target genes by ITRI-148 in VCaP cells. The transcriptomic effects of these AR-NTD degraders in enzalutamide-resistant C4-2B/MDVR cells closely mirror that of AR knockdown. Overall design: RNA-seq profiling of VCaP cells treated with DMSO or 1 µM ITRI-148 for 48 hours; and the profiling of enzalutamide-resistant C4-2B/MDVR cells treated with DMSO, 5 µM ITRI-90, 5 µM ITRI-148 or infected with Lentivirus carrying pLKO1 control vector or AR-knockdown shRNA.