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

• . 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

• , and to support a balanced gut microbiota [7]. In view of this pleiotropic role, FXR activation has emerged as a well-established pharmacological target for MASH [8]. Consequently, a diverse range of FXR agonists – categorized as bile acid derivatives, non-bile-acid steroidal agonists, non-steroidal

• FXR agonist, served as the lead compound for a series of derivatives, such as cilofexor (GS-9674). Unfortunately, these agonists have failed in clinical trials because of side effects such as itching or a failure to meet primary endpoints. Despite the failure of several FXR agonists to achieve the