RORγ (RAR-related orphan receptor gamma) is a protein of the nuclear receptor family of transcription factors. RORγ (RORγ1) and RORγt (RORγ2) are two isoforms, encoded by the same RORC gene. It exists in many tissues, but RORγt is restricted to the thymus. Thus, RORγt inhibitors have potential in the treatment of autoimmune diseases.
S18-000003 is a potent RORγt inhibitor, with anti-inflammatory activity. More information is as follows.
In one study, we get to know that S18-000003 exhibits potent activity against RORγt, with an IC50 of less than 30 nM for human RORγt. In cell-based assay, S18-000003 also dramatically inhibits human and mouse RORγt, with IC50s of 29 and 340 nM, respectively. Moreover, the inhibitor prevents differentiation of human and mouse T-helper 17 cells. The corresponding IC50 values are 13 and 200 nM, respectively.
In the other study, S18-000003 prevents the development of psoriatic skin inflammation by blocking IL-17 pathway. It suppresses different cells that can produce IL-17. The cell types include Tc17 cells, Th17 cells and dermal γδ T cells. In addition, S18-000003 reduces effect on psoriasis-like lesions in TPA-induced transgenic mice. Importantly, the inhibitor exerts low risk of thymic aberrations.
All in all, S18-000003 is a potent, orally bioavailable RORγt inhibitor. It has potential in the treatment for skin inflammatory disease, such as psoriasis.
References:
1. Sasaki Y, et al. Bioorg Med Chem Lett. 2018 Dec 1;28(22):3549-3553.
2. Imura C, et al. J Dermatol Sci. 2019 Mar;93(3):176-185.