WCF-598

WCF-598 is a RXRγ degrader (Kd: 234.2 nM) and an AR-V7 PROTAC degrader. It induces RXRγ degradation through the ubiquitin-proteasome pathway and can bind directly to RXRγ. Additionally, WCF-598 indirectly induces AR-V7 degradation by destabilizing the RXRγ-AR-V7 complex, reducing AR-V7 levels, and inhibiting the transcription of AR-V7 downstream target genes. It promotes tumor cell apoptosis, inhibits cell proliferation, activates the p53 signaling pathway, and impedes cell cycle progression. WCF-598 is applicable in prostate cancer research.

WCF-598 exhibits potent inhibitory effects on the viability of 22Rv1 cells with an IC50 of 13.56 nM and on VCaP-CRPC cells with an IC50 of 88.46 nM over 96 hours. Within a concentration range of 6.25-6400 nM for 48 hours, WCF-598 leads to a dose-dependent degradation of RXRγ protein in both 22Rv1 and VCaP-CRPC cells. Furthermore, in 22Rv1 cells, the compound causes a dose-dependent degradation of AR-V7 protein, with a DC50 of 122.0 nM observed after 48 hours. Over a period of 14 days, at concentrations between 100-400 nM, WCF-598 effectively and concentration-dependently inhibits the colony formation of 22Rv1 cells. Additionally, within 72 hours at the same concentration range, it induces apoptosis in 22Rv1 cells, as evidenced by increased levels of cleaved PARP, caspase-7, and elevated Caspase-3/7 activity. Moreover, WCF-598 activates p53 pathways and inhibits cell cycle-related pathways in 22Rv1 cells in a concentration-dependent manner over 48 hours.

WCF-598 (10-20 mg/kg; intraperitoneal injection; administered daily; 17 days) exhibits a dose-dependent inhibition on the growth of 22Rv1 castration-resistant prostate cancer (CRPC) xenograft tumors in NOD-SCID mice.