6tlm

Publication Abstract from PubMed

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 (RORgammat) 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 RORgammat. A compound library around the central thienopyrazole scaffold captured a clear structure-activity relationship, but the binding mechanism of this new class of RORgammat 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.

Elucidation of an allosteric mode-of-action for a thienopyrazole RORgammat inverse agonist.,de Vries RMJM, Meijer FA, Doveston RG, Brunsveld L ChemMedChem. 2020 Feb 13. doi: 10.1002/cmdc.202000044. PMID:32053744^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.