Abstract
The demand for allosteric targeting of nuclear receptors is high, but examples are limited, and structural information is scarce. The retinoic acid‐related orphan receptor gamma t (RORγt) is an important transcriptional regulator for the differentiation of T helper 17 cells for which the first, and some of the most promising, examples of allosteric nuclear receptor modulation have been reported and structurally proven. In a 2015 patent, filed by the pharmaceutical company Glenmark, a new class of small molecules was reported that act as potent inverse agonists for RORγt. A compound library around the central thienopyrazole scaffold captured a clear structure‐activity relationship, but the binding mechanism of this new class of RORγt modulators has not been elucidated. Using a combination of biochemical and X‐ray crystallography studies, here the allosteric mechanism for the inverse agonism for the most potent compound, classified in the patent as “example 13”, is reported, providing a strongly desired additional example of allosteric nuclear receptor targeting.
Highlights
Nuclear receptors (NRs) are a family of ligand-dependent transcription factors that constitute an important class of drug target.[1,2] Within this family, the retinoic acid-related orphan receptor gamma t (RORγt) has garnered much attention as an intervention point to treat autoimmune diseases such as multiple sclerosis, psoriasis and inflammatory bowel disease
In recent work to develop novel allosteric RORγt inverse agonists we reported the synthesis and inverse agonistic behavior of compound 13, which was used as a reference molecule.[16]
In a time-resolved FRET (TR-FRET) coactivator recruitment assay we reported that compound 13 effectively inhibited coactivator peptide binding, and the background constitutive activity of RORγt, in a dose-dependent manner with an IC50 value of 425 61 nM (Figure 2A).[16]
Summary
Nuclear receptors (NRs) are a family of ligand-dependent transcription factors that constitute an important class of drug target.[1,2] Within this family, the retinoic acid-related orphan receptor gamma t (RORγt) has garnered much attention as an intervention point to treat autoimmune diseases such as multiple sclerosis, psoriasis and inflammatory bowel disease. The structural characterization of new classes of allosteric RORγt inverse agonist is of great value in terms of better understanding SAR with respect to this allosteric pocket. It contributes to our growing conceptual understanding of NR allosteric modulation in general
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