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From ROR?t Agonist to Two Types of ROR?t Inverse Agonists.

ABSTRACT: Biaryl amides as new ROR?t modulators were discovered. The crystal structure of biaryl amide agonist 6 in complex with ROR?t ligand binding domain (LBD) was resolved, and both "short" and "long" inverse agonists were obtained by removing from 6 or adding to 6 a proper structural moiety. While "short" inverse agonist (8) recruits a corepressor peptide and dispels a coactivator peptide, "long" inverse agonist (9) dispels both. The two types of inverse agonists can be utilized as potential tools to study mechanisms of Th17 transcriptional network inhibition and related disease biology.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5807863 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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From RORγt Agonist to Two Types of RORγt Inverse Agonists.

Wang Yonghui Y Cai Wei W Tang Ting T Liu Qian Q Yang Ting T Yang Liuqing L Ma Yingli Y Zhang Guifeng G Huang Yafei Y Song Xiaoxia X Orband-Miller Lisa A LA Wu Qianqian Q Zhou Ling L Xiang Zhijun Z Xiang Jia-Ning JN Leung Stewart S Shao Liming L Lin Xichen X Lobera Mercedes M Ren Feng F

ACS medicinal chemistry letters 20180122 2

Biaryl amides as new RORγt modulators were discovered. The crystal structure of biaryl amide agonist 6 in complex with RORγt ligand binding domain (LBD) was resolved, and both "short" and "long" inverse agonists were obtained by removing from 6 or adding to 6 a proper structural moiety. While "short" inverse agonist (8) recruits a corepressor peptide and dispels a coactivator peptide, "long" inverse agonist (9) dispels both. The two types of inverse agonists ca ...[more]

PMID: 29456799

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