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.
Reference: