A-9758 is a RORγ ligand and selective RORγt inverse agonist (IC50: 5 nM) that effectively suppresses IL-17A release, Th17 differentiation, and Th17 effector function, significantly attenuating IL-23 driven psoriasiform dermatitis.

RORα:73 nM , RORβ:1370 nM , RORγt:5 nM

A-9758 inhibits RORγ transactivation in humans, mice, dogs, and rats (IC50s: 38 nM, 20 nM, 25 nM, and 64 nM, respectively). It exhibits a cofactor profile by recruiting co-repressors [NCoR1: EC50 = 60 nM, NCoR2: EC50 = 43 nM] and derecruiting co-activators [NCoA1: IC50 = 110 nM, PGC1α: IC50 = 49 nM]. A-9758 inhibits TCR-mediated IL-17A secretion with IC50s of 100 nM and 38 nM for human CD4+ T cells and in vitro differentiated mouse Th17 cells, respectively, and attenuates the differentiation and/or effector function of RORγt-expressing Th17 cells.