posted on 2023-11-20, 13:20authored byLixue Lu, Yafei Huang, Meiqi Song, Nannan Sun, Li Xia, Mingcheng Yu, Meiling Zhao, Ruomeng Qiu, Ji-an Chen, Yunpeng Zhao, Haojie Wang, Huimin Guo, Yan Li, Di Zhu, Yonghui Wang, Qiong Xie
The
master transcription factor receptor retinoic acid receptor-related
orphan receptor γt (RORγt) regulates the differentiation
of T-helper 17 (Th17) cells and the production of interleukin-17 (IL-17).
Activation of RORγt+ T cells in the tumor microenvironment
promotes immune infiltration to more effectively inhibit tumor growth.
Therefore, RORγt agonists provide a reachable approach to cancer
immunotherapy. Herein, a series of biaryl amide derivatives as novel
RORγt agonists were designed, synthesized, and evaluated. Starting
from the reported RORγt inverse agonist GSK805 (1), “functionality switching” and structure-based drug
optimization led to the discovery of a promising RORγt agonist
lead compound 14, which displayed potent and selective
RORγt agonist activity and significantly improved metabolic
stability. With excellent in vivo pharmacokinetic
profiles, compound 14 demonstrated robust efficacy in
preclinical tumor models of mouse B16F10 melanoma and LLC lung adenocarcinoma.
Taken together, current studies indicate that 14 deserves
further investigation as a potential lead RORγt agonist for
cancer immunotherapy.