Study On Small Molecule Ligands Of Retinoic Acid Receptor-related Orphan Receptor Gamma

RORs plays an important role in the regulation of the circadian rhythms,metabolic genes and syndrome.As ligand-dependent transcriptional factors,RORs associated with obesity and metabolic diseases,such as fatty degeneration,adipose tissue which related to inflammation,insulin resistance and autoimmune diseases.ROR?,a member of RORs,plays multiple roles in many physiological processes including growth,inflammation,circadian rhythm and lipid metabolism.RORy is widely expressed in many tissues such as liver,adipose and skeletal muscles.In mammals,RORy is required for the lymphoid and thymus.In this study,the prokaryotic expression was used to express the target protein RORy-LBD(residues 262-507).The protein was purified by nickel column affinity chromatography and gel filtration chromatography.In this study,12000 compounds provided by ChemDiv purchased,24 compounds were identified as RORy antagonists in the thermal stability shift assay(TSA).Of these,the hit compound CD9 was selected as a starting point for further structural optimization.In total,75 derivatives were designed,synthesized,and assessed in the bioassay of AlphaScreen,TSA and Luciferase.Several derivatives had better suppression of the ROR? basal transcriptional activity than the starting compound CD9.The most potent compounds 5,30 and 31 inhibited RORy with IC50 values of 70-950 nM.Their RORy antagonism was 60-fold higher than that of the hit compound CD9.These compounds thus represent a promising starting point for developing potent small molecule RORy antagonist with the potential for the treatment of related diseases.