RORγ antagonists and inverse agonists: a patent review

Abstract

The transcription factor RORγ plays a critical role in the expression of pro-inflammatory cytokine interleukin IL-17 and is therefore an attractive target for the treatment of inflammatory diseases. Interest in this molecular target has been heightened by the advancement of orally and topically administered RORγ modulators into clinical trials. Areas covered: The present review seeks to summarize published patent applications from assignee companies that have disclosed Investigational New Drug (IND) filings for small molecule RORγ/RORγt antagonists and inverse agonists. Expert opinion: The field of RORγ research is extremely competitive, with the majority of companies targeting psoriasis as the primary disease indication. Vitae Pharmaceuticals is currently the most advanced, with a potential first-in-class oral RORγ-modulator for the treatment of psoriasis. Future efforts will likely expand into potential applications of RORγ-modulators in the lesser explored immune-related areas of rheumatoid arthritis, type 1 diabetes, lupus, and irritable bowel disorder, as well as cancer immunotherapy and castration-resistant prostate cancer.

Circulating CD14+HLA‐DR−/low Myeloid‐Derived Suppressor Cells as Potential Biomarkers for the Identification of Psoriasis TCM Blood‐Heat Syndrome and Blood‐Stasis Syndrome

“…Another possibility is that Mo-MDSCs downregulate IL-17A levels in circulation [31]. e transcription factor ROR-c plays a critical role in the expression of proinflammatory cytokine IL-17 in patients with psoriasis [32] and is, therefore, an attractive target for the treatment of psoriasis [33]. In the current study, we found the ROR-c mRNA levels were significantly increased in the PBMCs of psoriasis patients when compared to controls.…”

RORγ regulates the NLRP3 inflammasome

“…A number of ROR␥ inverse agonists are under clinical development based on the ability of ROR␥ to suppress T h 17 cell development and function (14). Our group, as well as the Littman group (13), were the first to identify ROR␥ inverse agonists and characterize their ability to suppress T h 17 cell development/function and reduce the severity of autoimmune disease in rodent models (7).…”

“…We and others have demonstrated that targeting inhibition of ROR␥ activity with inverse agonists is an effective method for suppressing T h 17 cell differentiation and function as well as treatment of autoimmune diseases in rodent models (7,(11)(12)(13). Several of these ROR␥ inverse agonists are now being evaluated in clinical trials to treat autoimmune diseases such as psoriasis (14). Beyond T h 17 lymphocytes, ROR␥ is also expressed in innate immune cells, such as macrophages and natural killer cells, suggesting a wider role for ROR␥ beyond T h 17 cell differentiation and function in regulation of immunity.…”

Structural States of RORγt: X‐ray Elucidation of Molecular Mechanisms and Binding Interactions for Natural and Synthetic Compounds

“…[10] Overviews summarizing the current knowledge of structural biology aroundR ORgta gonists, antagonists, and inverse agonists (including orthosteric and allosteric binders)h aveb een published recently. [10] Overviews summarizing the current knowledge of structural biology aroundR ORgta gonists, antagonists, and inverse agonists (including orthosteric and allosteric binders)h aveb een published recently.…”

“…In the last few years several companies have patented chemicals eries, mainly to discovera nd optimize inverse agonists, for both oral and topicala dministration. [10] Overviews summarizing the current knowledge of structural biology aroundR ORgta gonists, antagonists, and inverse agonists (including orthosteric and allosteric binders)h aveb een published recently. [4,11] Herein we report eight new X-ray structures for natural and synthetic compounds including selected examples from the patent literature.…”