Design, synthesis, and biological evaluation of FXR/ASK1 dual-target modulators

• Xi Zhang,
• Jingyan Wang,
• Ziqiang Zhao,
• Caiyi Wang,
• Zenghui Ye,
• Wei-Yuan Ma,
• Jian-Xing Xu and
• Fengzhi Zhang

Beilstein J. Org. Chem. 2026, 22, 771–781, doi:10.3762/bjoc.22.59

• dysfunction-associated fatty liver disease (MAFLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). GW4064 and GS-4997 are effective regulators for FXR and ASK1, respectively. Through the effective functional group splicing strategy, a new dual-target modulator is designed

• . Compound Z8, which acts on both targets, was found to more potently reduce intracellular lipid droplet accumulation in OA-treated HepG2 cells than the FXR agonist GW4064 and the ASK1 inhibitor selonsertib (GS-4997). Keywords: ASK1 inhibitors; FXR agonists; FXR/ASK1 dual-target modulators; MASH

• , inflammation, and fibrosis [1]. MAFLD is a clinical entity that encompasses a spectrum of disease, with metabolic dysfunction-associated steatohepatitis (MASH) denoting a more advanced form [2]. The condition is characterized by steatosis, hepatocyte injury, and inflammation [3], which can progress to fibrosis