Niclo-Click PROTAC 5

Niclo-Click PROTAC 5 is an experimental proteolysis-targeting chimera (PROTAC) designed to target the androgen receptor (AR) for degradation in the treatment of prostate cancer, particularly castration-resistant prostate cancer (CRPC). It is a hetero-bifunctional molecule consisting of niclosamide, which serves as the AR-binding ligand, and VHL-032, which acts as the ligand for the Von Hippel-Lindau (VHL) E3 ligase. These two components are connected via a linker synthesized using click chemistry. Although designed to initiate the ubiquitin-proteasome pathway for protein degradation, preclinical Western Blotting assays indicated that Niclo-Click PROTAC 5 does not effectively degrade the androgen receptor at concentrations up to 1 µM. Despite the lack of AR degradation, the compound exhibits selective antiproliferative activity against AR-positive prostate cancer cell lines such as LNCaP and 22Rv1, as well as the AR-negative PC-3 line, while failing to inhibit DU145 cells. This suggests that its mechanism for suppressing cancer cell proliferation is independent of the intended PROTAC-mediated AR degradation.