A-9758

A-9758 is a RORγ ligand and a potent, selective RORγt inverse agonist (IC50=5 nM), and exhibits robust potency against IL-17A release. A-9758 is effective in suppressing both Th17 differentiation and Th17 effector function. A-9758 significantly attenuates IL-23 driven psoriasiform dermatitis and is effective in blocking skin and joint inflammation[1]. IC50: 5 nM (RORγt), 73 nM (RORα), 1370 nM (RORβ)[1]

A-9758 inhibits human, mouse, dog and rat RORγ transactivation (IC50=38 nM, 20 nM, 25 nM and 64 nM, respectively)[1].A-9758 displays a cofactor profile in recruiting co-repressors (NCoR1: EC50=60 nM, NCoR2: EC50=43 nM) and derecruiting co-activators (NCoA1: IC50=110 nM, PGC1α: IC50=49 nM)[1].A-9758 inhibits TCR-mediated IL-17A secretion with an IC50 of 100 and 38 nM for human CD4+ T cells and in vitro differentiated mouse Th17 cells, respectively. A-9758 attenuates the differentiation of RORγt expressing Th17 cells and/or their effector function[1].

[1]. Gauld S, et al. Inhibition of IL-23 mediated inflammation with a novel small molecule inverse agonist of RORgt. J Pharmacol Exp Ther. 2019 Aug 2. pii: jpet.119.258046.