Modulators of the Nuclear Receptor Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc)

Abstract

As the biology surrounding the nuclear receptor retinoic acid receptor-related orphan receptor-gamma (RORγ or RORc) continues to evolve, significant effort has been invested in discovering modulators of this potentially important target for the treatment of metabolic and immunological diseases. Several major pharmaceutical and biotechnology companies have disclosed RORc inhibitors or partnered with other players in the field. In this perspective, we discuss both the biology and the underlying structural biology of RORc, and summarize the RORc modulators disclosed in the scientific and patent literature.

Th17 plasticity: pathophysiology and treatment of chronic inflammatory disorders

“…Finally, the recent discovery of several RORc inhibitors could represent in the future a good opportunity to target several cell types, since RORC is expressed by Th17, Th17/Th1, Th17/Th2, and also non-classic Th1 subsets [38]. Nevertheless, the recent finding that RORc expression might play a protective role in human diseases by Severe asthma…”

Discovery of N -(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists

“…[7][8][9][10][11][12][13] A few small molecule inhibitors against RORt have been reported in literature. 14 Digoxin, 15 SR1001 16 and Ursolic acid 17 were firstly reported to inhibit RORt and ameliorate EAE in mice via intraperitoneal administration. Afterwards, more small molecular RORt inhibitors [18][19][20][21][22][23][24][25][26] were disclosed and some of them were shown to suppress Th17 cell differentiation in vitro.…”

Discovery of biaryl carboxylamides as potent RORγ inverse agonists

“…Thus RORγ has garnered significant attention as a small molecule therapeutic target. 2,3,4 RORγt is essential in the development of secondary lymphoid tissues and plays a pivotal role in the development and function of multiple pro-inflammatory lymphocyte lineages including T H 17cells, LTi cells, γδT cells and iNKT cells. 2,3,4 These cells and the cytokines they produce, including IL-17 and IL-22, have been implicated in many chronic immune-mediated diseases.…”

“…2,3,4 RORγt is essential in the development of secondary lymphoid tissues and plays a pivotal role in the development and function of multiple pro-inflammatory lymphocyte lineages including T H 17cells, LTi cells, γδT cells and iNKT cells. 2,3,4 These cells and the cytokines they produce, including IL-17 and IL-22, have been implicated in many chronic immune-mediated diseases. Increased numbers of RORγt-expressing cells and RORγt regulated cytokines, including IL-17 and IL-22, have been observed in the tissues and circulation of patients suffering from multiple immune-mediated pathologies including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and psoriasis.…”