De Novo Design of an Androgen Receptor DNA Binding Domain Targeted peptide PROTAC for Prostate Cancer Therapy

AbstractAndrogen receptor splice variant 7 (AR V7), one of the major driving factors, is the most attractive drug target in castration resistant prostate cancer (CRPC). Currently, no available drugs efficiently target AR V7 in clinical practice. The DNA binding domain (DBD) is indispensable for the transcriptional activity of AR full length and AR splice variants, including AR V7. Based on the homodimerization structure of the AR DBD, a novel peptide based proteolysis targeting chimera (PROTAC) drug is designed to induce AR and AR V7 degradation in a DBD and MDM2 dependent manner, without showing any activity on other hormone receptors. To overcome the short half life and poor cell penetrability of peptide PROTAC drugs, an ultrasmall gold (Au) peptide complex platform to deliver the AR DBD PROTAC in vivo is developed. The obtained Au AR pep PROTAC effectively degrades AR and AR V7 in prostate cancer cell lines, particularly in CWR22Rv1 cells with DC 50 values 48.8 and 79.2 nM, respectively. Au AR pep PROTAC results in suppression of AR levels and induces tumor regression in both enzalutamide sensitive and resistant prostate cancer animal models. Further optimization of the Au AR pep PROTAC can ultimately lead to a new therapy for AR V7 positive CRPC.A novel peptide PROTAC targeting androgen receptor DNA binding domain via AI Rosetta assisted design for castration resistant prostate cancer therapy is presented.