PROTAC ERRα Degrader-3 is a highly effective and selective von Hippel-Lindau-based ligand that efficiently degrades the ERRα protein, reducing its levels by >80% at a concentration of 30 nM. Notably, this compound shows no activity against the ERRβ and ERRγ proteins.

PROTAC ERRα Degrader-3 (compound 6c; 0.3 nM-10 μM; 4 hours) effectively induces the degradation of ERRα in a dose-dependent manner, achieving significant degradation with doses as low as 3.0 nM within 4 hours. This compound also significantly reduces the levels of ERRα downstream target genes, such as ATP5B, medium-chain acyl CoA dehydrogenase (MCAD), and pyruvate dehydrogenase kinase 4 (PDK4), in MDA-MB-231 cells following 24 hours of exposure. Furthermore, PROTAC ERRα Degrader-3 disrupts the protein-protein interaction between ERRα and the PGC-1α peptide, marked by an IC50 of 12.67 nM, and induces approximately 96% degradation of the ERRα protein at a concentration of 100 nM after 4 hours. Western Blot analysis in MDA-MB-231 cells across a range of concentrations (0.3 nM to 10 μM) and a 4-hour incubation period corroborates the dose-dependent mechanism of ERRα degradation.