Identification of New Small Molecule Inducers of Estrogen-related Receptor α (ERRα) Degradation

A series of (E)-3-(4-((2,4-bis(trifluoromethyl)benzypoxy)-3-methoxyphenyl)-2-cyanoacrylamide derivatives were designed and synthesized as new estrogen-related receptor alpha (ERR alpha) degraders based on the proteolysis targeting chimera (PROTAC) concept. One of the representative compounds 6c is capable of specifically degrading ERR alpha protein by >80% at a relatively low concentration of 30 nM, becoming one of the most potent and selective ERR alpha degraders to date. Compound 6c could be utilized as a new powerful research tool for further biological investigation of ERR alpha.