1099073-00-3Relevant articles and documents
Discovery of tert-amine-based RORγt agonists
Qiu, Ruomeng,Yu, Mingcheng,Gong, Juwen,Tian, Jinlong,Huang, Yafei,Wang, Yonghui,Xie, Qiong
, (2021/07/26)
The nuclear receptor retinoic acid receptor-related orphan receptor gamma-t (RORγt) is a transcription factor regulating Th17 cell differentiation and proliferation from naive CD4+ T cells. Since Th17 cells have demonstrated the antitumor efficacy by eliciting remarkable activation of CD8+ T cells, RORγt agonists could be applied as potential small molecule therapeutics for cancer immunotherapy. Based on the previously reported RORγt agonist 1 and its resolved co-crystal structure, a series of new tertiary amines were designed, synthesized and biologically evaluated, yielding optimal moieties with improved chemical properties and biological responses. The combination of these optimal moieties resulted in identification of novel RORγt agonists such as 8b with further elevated RORγt agonism responses at a target-based level as well as in cell-based assays, which provided some structural knowledge for further optimization of RORγt agonists as small molecule therapeutics for cancer immunotherapy.
Discovery of tertiary amine and indole derivatives as potent RORγt inverse agonists
Yang, Ting,Liu, Qian,Cheng, Yaobang,Cai, Wei,Ma, Yingli,Yang, Liuqing,Wu, Qianqian,Orband-Miller, Lisa A.,Zhou, Ling,Xiang, Zhijun,Huxdorf, Melanie,Zhang, Wei,Zhang, Jing,Xiang, Jia-Ning,Leung, Stewart,Qiu, Yang,Zhong, Zhong,Elliott, John D.,Lin, Xichen,Wang, Yonghui
supporting information, p. 65 - 68 (2014/02/14)
A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists.
