Inhibitors of RORγt
Recently, several inhibitors of RORγt have been identified that effectively restrict the function and differentiation of pro-inflammatory T helper (Th)17 cells. They appear to hold therapeutic potential in inflammation & autoimmunity.
Nuclear hormone receptors (NHRs) form a family of transcription factors that are composed of modular protein structures with DNA- and ligand-binding domains (DBDs and LBDs). The DBDs confer gene target site specificity, whereas LBDs serve as control switches for NHR function. For many NHRs, both endogenous and synthetic small molecule ligands bind to small pockets within the LBDs, resulting in conformational changes that regulate transcriptional activity.
This property of NHRs has been exploited by the pharmaceutical industry for therapeutic targeting of a wide variety of diseases, ranging from inflammatory diseases and cancer to endocrine and metabolic diseases.
Recent studies have shown that Th17 cells have key pro-inflammatory roles in cancer and a variety of autoimmune diseases. In both mouse and human, not only Th17 cells, but also other immune cells, e.g. cells with the γδ T cell receptor and various innate lymphoid cells (ILCs) that express IL-17 and/or IL-22, are distinguished by their expression of RORγt. RORγt is required for the induction of IL-17 transcription and for the manifestation of Th17-dependent autoimmune disease in mice.
The transcription factor RORγt belongs to the nuclear receptor superfamily – consisting of 48 members that serve as ligand-activated transcription factors translating extracellular or intracellular signals into a transcriptional response. RORγt is the immune cell-specific isoform of RORγ (retinoic acid receptor-related orphan nuclear receptor gamma).
This has garnered considerable interest because it represents the master transcription factor essential for the development of Th17cells (I Ivanov et al, Cell, 2006, 126:1121; L Klotz & Knolle P, FEBS Lett, 2011, 585:3764; JR Huh & Littman DR, Eur J Immunol, 2012, 42:2232).
The Th17cells, discovered in 2005, are now considered as key players in the pathogenesis of numerous inflammatory/autoimmune diseases, including rheumatoid arthritis, Guillain-Barré syndrome, Takayasu arteritis, and perhaps atherosclerosis and fibromyalgia.
By performing a small-scale small molecule screen with these insect cell-based reporter systems, the cardiac glycoside digoxin was identified as a specific inhibitor of RORγt transcriptional activation. Digoxin inhibited murine Th17-cell differentiation without affecting other T-cell lineages.
By modifying the Liver X Receptor (LXR) ligand T0901317, Griffin and Burris initially identified a small molecule, SR1001, which inhibited both RORα and RORγt activities. Further chemical modification led to the development of a RORγ/γt specific inhibitor, SR2211, which suppressed IL-17 production in the mouse T-cell lymphoma EL-4.
By carrying out small-scale small molecule screens with primary human Th17 or EL-4 cells, ursolic acid and azole-type fungicides were identified as RORγt or RORα/RORγt inhibitors, respectively. Likewise, these compounds inhibited IL-17 production.
Importantly, treatment of animals with digoxin, SR1001, or ursolic acid was shown to not only delay onset, but also to reduce severity of the mouse model of multiple sclerosis, experimental autoimmune encephalomyetis
Along these lines, the recently developed small molecule inhibitors of RORγt may represent a promising therapeutic target in many inflammatory/autoimmune disorders. It remains to be seen whether these inhibitors will be effective in clinical applications and settings (JR Huh & Littman DR, Eur J Immunol, 2012, 42:2232; F Isono, S Fujita-Sato & Ito S, Drug Discov Today, 2014, 19:1205).
Recently, Lead Pharma, a company focused on the development of small molecule drugs, announced that it has achieved the first milestone under its research collaboration with Sanofi. The collaboration includes the development of small molecules targeting the transcription factor RORγt, aimed at the treatment of a broad range of autoimmune disorders.
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