Elucidation of an Allosteric Mode of Action for a Thienopyrazole RORγt Inverse Agonist.,ChemMedChem

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Elucidation of an Allosteric Mode of Action for a Thienopyrazole RORγt Inverse Agonist.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-03-12 , DOI: 10.1002/cmdc.202000044
Rens M J M de Vries ₁ , Richard G Doveston _{1,

2} , Femke A Meijer ₁ , Luc Brunsveld ₁

Affiliation

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.

中文翻译：

阐明噻吩并吡唑 RORγt 反向激动剂的变构作用模式。

对核受体变构靶向的需求很高，但例子有限，并且结构信息稀缺。视黄酸相关孤儿受体 γt (RORγt) 是辅助 T 细胞 17 细胞分化的重要转录调节因子，第一个也是一些最有希望的变构核受体调节实例已被报道并在结构上得到证实。制药公司 Glenmark 于 2015 年提交的一项专利中报道了一种新型小分子，可作为 RORγt 的有效反向激动剂。围绕中心噻吩并吡唑支架的化合物库捕获了清晰的结构-活性关系，但这种新型 RORγt 调节剂的结合机制尚未阐明。结合生化和 X 射线晶体学研究，本文报道了最有效化合物的反向激动的变构机制，在专利中分类为“实施例 13”，提供了强烈期望的变构核受体靶向的额外例子。

更新日期：2020-03-12

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