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Elucidation of an allosteric mode‐of‐action for a thienopyrazole RORγt inverse agonist

DOI: 10.1002/cmdc.202000044 DOI Help

Authors: Rens M. J. M. De Vries (Technische Universiteit Eindhoven) , Femke A. Meijer (Technische Universiteit Eindhoven) , Richard G. Doveston (Technische Universiteit Eindhoven) , Luc Brunsveld (Technische Universiteit Eindhoven)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemmedchem

State: Published (Approved)
Published: February 2020

Open Access Open Access

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.

Journal Keywords: Nuclear Receptors; RORγt; Allosteric Modulators; Structure Elucidation; Drug Discovery

Subject Areas: Chemistry, Medicine

Instruments: I24-Microfocus Macromolecular Crystallography


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