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Discovery of the First-in-Class Intestinal Restricted FXR and FABP1 Dual Modulator ZLY28 for the Treatment of
Qiang Ren1,2, Ya Chen1, Zongtao Zhou1,3,2,4
1School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Abstract:
The prevalence of nonalcoholic steatohepatitis (NASH) is increasing rapidly worldwide, and NASH has become a serious problem for human health. Recently, the selective activation of the intestinal farnesoid X receptor (FXR) was considered as a more promising strategy for the treatment of NASH with lesser side effects due to reduced systemic exposure. Moreover, the inhibition of intestinal fatty acid binding protein 1 (FABP1) alleviated obesity and NASH by reducing dietary fatty acid uptake. In this study, the first-in-class intestinal restricted FXR and FABP1 dual-target modulator ZLY28 was discovered by comprehensive multiparameter optimization studies. The reduced systemic exposure of ZLY28 might provide better safety by decreasing the on- and off-target side effects in vivo. In NASH mice, ZLY28 exerted robust anti-NASH effects by inhibiting FABP1 and activating the FXR-FGF15 signaling pathway in the ileum. With the above attractive efficacy and preliminary safety profiles, ZLY28 is worthy of further evaluation as a novel anti-NASH agent.
Insights
A new drug, ZLY28, targets both farnesoid X receptor (FXR) and fatty acid binding protein 1 (FABP1) in the intestine to treat nonalcoholic steatohepatitis (NASH). This dual-action approach shows promise for effectively managing NASH with potentially fewer side effects.
Area of Science:
- Hepatology
- Gastroenterology
- Pharmacology
Background:
- Nonalcoholic steatohepatitis (NASH) prevalence is rising globally, posing a significant health concern.
- Targeting intestinal farnesoid X receptor (FXR) offers a promising therapeutic strategy for NASH with reduced systemic side effects.
- Inhibiting intestinal fatty acid binding protein 1 (FABP1) can mitigate obesity and NASH by limiting dietary fat absorption.
Purpose of the Study:
- To discover and characterize ZLY28, a novel dual-target modulator for intestinal FXR and FABP1.
- To evaluate the efficacy and preliminary safety profile of ZLY28 in a preclinical NASH model.
Main Methods:
- Comprehensive multiparameter optimization was employed to discover ZLY28.
- The anti-NASH effects of ZLY28 were assessed in a mouse model of NASH.
- Mechanism of action involved inhibition of FABP1 and activation of the FXR-FGF15 signaling pathway in the ileum.
Main Results:
- ZLY28 demonstrated robust anti-NASH effects in mice.
- The drug inhibited FABP1 and activated the FXR-FGF15 pathway in the ileum.
- Reduced systemic exposure of ZLY28 suggests a potentially improved safety profile.
Conclusions:
- ZLY28 is the first-in-class intestinal restricted FXR and FABP1 dual-target modulator.
- ZLY28 exhibits significant efficacy in a preclinical NASH model.
- ZLY28 warrants further investigation as a novel therapeutic agent for NASH.
