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Elucidation of an Allosteric Mode of Action for a Thienopyrazole RORγt Inverse Agonist
Author(s) -
Vries Rens M. J. M.,
Doveston Richard G.,
Meijer Femke A.,
Brunsveld Luc
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000044
Subject(s) - allosteric regulation , inverse agonist , nuclear receptor , rar related orphan receptor gamma , orphan receptor , allosteric modulator , chemistry , retinoic acid , receptor , agonist , mode of action , mechanism of action , stereochemistry , pharmacology , microbiology and biotechnology , computational biology , biochemistry , biology , transcription factor , gene , in vitro
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.