A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques
Xiao‐Jing Zhang, Yan‐Xiao Ji, Xu Cheng, Yanjie Cheng, Hailong Yang, Junyong Wang, Ling‐Ping Zhao, Yongping Huang, Dating Sun, Hui Xiang, Lijun Shen, Penglong Li, Junpeng Ma, Ruifeng Tian, Juan Yang, Xinxin Yao, Haibo Xu, Rufang Liao, Li Xiao, Peng Zhang, Xin Zhang, Guang‐Nian Zhao, Xi Wang, Manli Hu, Song Tian, Juan Wan, Jingjing Cai, Xinliang Ma, Qingbo Xu, Yibin Wang, Rhian M. Touyz, Peter P. Liu, Rohit Loomba, Zhi‐Gang She, Hongliang Li
Abstract
macaque therapeutic models. The anti-NASH efficacy of IMA-1 was comparable to ACC inhibitor in both species. Protein docking simulations and following functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface instead of inhibiting ALOX12 lipoxygenase activity. IMA-1 treatment did not elicit hyperlipidemia, a known side effect of direct inhibition of ACC enzymatic activity, in both mice and macaques. These findings provide proof of concept across multiple species for the use of small molecule–based therapies for NASH.