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

• of insulin resistance, inflammation, and hepatic steatosis [15]. The most advanced ASK1 inhibitor in clinical development is the compound celonsertib (Scheme 2). Following this, a series of new ASK1 inhibitors were derived using selonsertib as a lead compound in a variety of structure-optimized ways

• followed by the appropriate post hoc test; ***p < 0.001 versus OA control. Additional pairwise comparisons between Z8 and the positive-control groups are described in the text. (C) Cell viability at 10 μM under the same treatment conditions. Steroidal and nonsteroidal FXR agonists. ASK1 inhibitors. Dual