In our cancer blog, we have introduced a large number of PROTACs. A1874 exhibits a nultin-based BRD4-degrading PROTAC. MT-802 shows as a PROTAC degrader of BTK for C481S mutant CLL treatment. dBET6 is also an orally active PROTAC degrader of BET and others. As a protein degradation technique, PROTAC has gained momentum as a new small-molecule therapeutic strategy. Scientists have developed many small-molecule inhibitors based-on PROTAC. Today, I’d like to introduce another novel PROTAC member, ARD-266.

Androgen receptor (AR) becomes a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Xin Han., et al designed and synthesized a highly potent small-molecule PROTAC AR degrader. In their past study, they have reported the discovery of 1 (ARD-61) as a highly potent and efficient PROTAC AR degrader. ARD-61, which achieves DC50 (concentration needed to degrade 50% of AR protein) values of 1-10 nM in LNCaP and VCaP AR+ prostate cancer cell lines. Later, they resulted in the discovery of 11 (ARD-266), which effectively induces degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1 prostate cancer cell lines with DC50 values of 0.2-1 nM.

In vitro, ARD-266 (Compound 11; 100 nM; 1-24 hours; LNCaP and VCaP cells) treatment effectively reduces the AR protein level within 3 h and achieves near-complete AR elimination with a 6 h treatment in the LNCaP cells. Additionally, ARD-266 (Compound 11; 1-10000 nM; 24 hours; LNCaP cells) treatment effectively suppresses the expression of PSA, TMPRSS2, and FKBP5 genes in a dose-dependent manner and is capable of reducing the mRNA levels of PSA, TMPRSS2, and FKBP5 genes by >50% at 10 nM in the LNCaP cell line.

Surprisingly, ARD266 is capable of reducing the AR protein level by >95% in these AR+ prostate cancer cell lines and effectively reduces AR-regulated gene expression suppression.

More in vivo studies are still needed for further validation of ARD266.


Han X, et al. Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands. J Med Chem. 2019 Dec 26;62(24):11218-11231.