Design,synthesis And Biological Evaluation Of Small-molecule Proteolysis Targeting Chimera(PROTAC)Degrader Of Estrogen Related Receptor

It is known that the“occupancy-driven”inhibition paradigm plays an important role in the pharmacological activity of small-molecule drugs.This mean that drug molecules need to occupy active or regulatory sites of targeted proteins.For decades,this kind of concept has remained largely unchanged.Generally,effective efficacious inhibition(IC₉₀)need high concentrations of drugs,which inevitably lead to off-target effects.At the same time,proteins with active and regulatory sites are recognized as“druggable”proteins,and medicinal chemists alway focus their attention on them.However,less than 20%of the approximately 20,300 known human proteins are recognized as“druggable”targets.Therefore,the definition of“druggable”proteome greatly limits the number of drug targets.Basing on the conception of"occupation-driven"inhibition,a new drug development strategy,named proteolytic targeting chimera?PROTACs?,has emerged recently and become the focus of attention.Unlike most of small-molecule drugs which just occupy the active site and inhibit the functions of targeted proteins,PROTACs mimic the natural degradation process caused by cellular proteasome,directly eliminating disease-causing proteins.It is“event-driven”pharmacological model of PROTACs that enable PROTACs to degrade superstoichiometric amounts of the target protein catalytically.What's more,the excellent selectivity and capacity to abolish the functions of“undruggable”targets by degradation make PROTACs a great potential drug research strategy.Estrogen-related Receptors?ERRs?belong to orphan nuclear receptor superfamily.Three isoforms of ERRs?ERR?,ERR?,ERR??have been identified to date.ERR?,the most studied one,is widely distributed in metabolic tissues and cancer tissues.Its capacity to regulate metabolism and energy stress in microenvironment of solid tumors make it a potential target for solid tumors.In my view,my project is a combination of ERR?research and PROTACs.Herein,I show my design,synthesis,and evaluation of a new series of ERR?_PROTACs.One of the representative compounds 13c is capable of specifically degrading ERR?protein by>80%at a relatively low concentration of 30 nM,becoming one of the most potent and selective ERR?degraders to date.Compound 13c could be utilized as new powerful research tool for further biological investigation of ERR?.