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

Area of Science:

• Hepatology
• Pharmacology
• Molecular Biology

Background:

• Metabolic dysfunction-associated fatty liver disease (MAFLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), require novel therapeutic strategies.
• Dual modulation of Farnesoid X receptor (FXR) and apoptosis signal-regulating kinase 1 (ASK1) presents a promising approach for treating these conditions.
• Existing regulators like GW4064 (FXR agonist) and GS-4997 (ASK1 inhibitor) show individual efficacy.

Purpose of the Study:

• To design and synthesize a novel dual-target modulator for FXR and ASK1.
• To evaluate the efficacy of the new compound in reducing intracellular lipid accumulation in a cellular model of fatty liver disease.

Main Methods:

• A functional group splicing strategy was employed to design a dual-target modulator.
• Compound Z8 was synthesized, targeting both FXR and ASK1.
• OA-treated HepG2 cells were used to assess intracellular lipid droplet accumulation.

Main Results:

• Compound Z8 demonstrated potent reduction of intracellular lipid droplet accumulation in OA-treated HepG2 cells.
• Z8's efficacy in reducing lipid accumulation surpassed that of the FXR agonist GW4064 and the ASK1 inhibitor selonsertib (GS-4997).

Conclusions:

• The novel dual-target compound Z8 effectively reduces lipid accumulation, showing greater potency than single-target agents.
• Z8 represents a promising therapeutic candidate for MAFLD and MASH, warranting further investigation.