ARD-266

ARD-266 potently induces cellular degradation of Androgen receptor at nanomolar concentrations within three hours of treatment in several tested human cell lines. As expected, degradation resulted in downregulation of Androgen receptor target genes. Effects of ARD-266 were prevented by pretreatment of cells with an AR antagonist, a VHL ligand or inhibitors of an E1 enzyme or the proteasome, suggesting that AR-266 is a true PROTAC degrader of Androgen receptor. Proteome-wide selectivity of ARD-266 has not been established and this limits the utility of this probe as a general tool to study Androgen receptor-specific downregulation.

This probe demonstrated degradation of AR in LNCaP cells with good DC50 and Dmax values. A western blot assay with a defined time course of five timepoints demonstrated degradation of AR, with clear target engagement shown after pretreatment with AR antagonists. However, the selectivity of the probe was not demonstrated. More biological data, and in vivo data, would help to increase the rating of this probe. There are other AR PROTACs that should be used rather than this probe.