GSK805

GSK805 is an inverse agonist of retinoic acid receptor-related orphan receptor γt (RORγt; IC₅₀ = 3.98 nM in a FRET assay).¹ It inhibits naïve CD4⁺ T cell differentiation into T helper 17 (Th17) cells induced by IL-6, TGF-β1, and IL-23 when used at a concentration of 0.5 µM.² GSK (2.5 µM) reduces viability in MDA-MB-468 breast cancer cells.³ It decreases levels of cholesterol in HCC70 epithelial breast cancer cells when used at a concentration of 2.5 µM. GSK805 (10 mg/kg per day) reverses hindlimb weakness and paralysis in a mouse model of experimental autoimmune encephalitis (EAE) induced by myelin oligodendrocyte glycoprotein (33-55) (MOG_33-55) and complete Freund's adjuvant.²

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1. Wang, Y., Cai, W., Cheng, Y., et al. Discovery of biaryl amides as potent, orally bioavailable, and CNS penetrant RORγt inhibitors. ACS Med. Chem. Lett. 6(7), 787-792 (2015).

2. Xiao, S., Yosef, N., Yang, J., et al. Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 40(4), 477-489 (2014).

3. Cai, D., Wang, J., Gao, B., et al. RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype. Nat. Commun. 10(1), (2019).