Retinoid-Acid Receptor-related Orphan Receptor gamma t (RORγt) Program

RORγt inverse agonists for the treatment of autoimmune diseases

RORγt is a highly attractive target for the treatment of autoimmune diseases like Psoriasis or Rheumatoid Arthritis - for which no curative or at least satisfying & cost-effective treatment is available.

RORγt controls the differentiation of a major contributor to chronic inflammation in these diseases, namely the TH17 cells. Inhibition of RORγt has the potential to selectively suppress TH17 driven chronic inflammation while leaving the remaining immune system intact. Thus, the identification of RORγt inhibitors opens new avenues for the development of more efficacious and selective drugs against autoimmune diseases.

As of 2013, the RORγt program is partnered with Janssen Biotech Inc., a market leader in the field of innovative autoimmune disease treatments. The partnership is a combination of Phenex's nuclear receptor know-how and the immunology & development expertise of Janssen to develop new RORγt based treatments for autoimmune diseases.

Selected publications:

Identification and biological evaluation of thiazole-based inverse agonists of RORγt.
Gege C, Cummings MD, Albers M, Kinzel O, Kleymann G, Schlüter T, Steeneck C, Nelen MI, Milligan C, Spurlino J, Xue X, Leonard K, Edwards JP, Fourie A, Goldberg SD, Hoffmann T.
Bioorg Med Chem Lett. 2018 May 15;28(9):1446-1455. Epub 2018 Apr 3.
Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.
Xue X, Soroosh P, De Leon-Tabaldo A, Luna-Roman R, Sablad M, Rozenkrants N, Yu J, Castro G, Banie H, Fung-Leung WP, Santamaria-Babi L, Schlüter T, Albers M, Leonard K, Budelsky AL, Fourie AM.
Sci Rep. 2016 Dec 1;6:37977.
Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt.
Gege C, Schlüter T, Hoffmann T.
Bioorg Med Chem Lett. 2014 Nov 15;24(22):5265-7. Epub 2014 Sep 28.