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<p>The fatty acid-binding protein 1 (FABP1) has drawn increasing attention as a promising target for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). However, efforts to validate pharmacological effects of FABP1 are restricted by the lack of relevant inhibitors. Herein, we identified the lead compound <b>1</b> with potent inhibition on FABP1 through screening from our in-house library. Further comprehensive structure-activity relationship (SAR) study based on compound <b>1</b> resulted in the identification of the optimal compound <b>12</b> (IC<sub>50</sub> = 3.6 µM). Moreover, compound <b>12</b> exerted stronger efficacy on reducing hepatic lipid accumulation, inflammation and fibrosis than that of clinical candidate GFT505 in MASH models. In addition, compound <b>12</b> significantly inhibited fibrosis-related gene expression in TGF-β treated hepatic stellate cells and exerted stronger effects than Pirfenidone in CCl<sub>4</sub>-induced liver fibrosis mice model. These results indicated that compound <b>12</b> may serve as a novel FABP1 inhibitor for the treatment of MASH and liver fibrosis.</p>

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Discovery of novel FABP1 inhibitors for the treatment of metabolic dysfunction-associated steatohepatitis and hepatic fibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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  • Zongtao Zhou,
  • Zhonghui Luo,
  • Xudong Lv,
  • Lianru Chen,
  • Zhihong Qin,
  • Qi Ma,
  • Zheng Li,
  • Deyang Kong

摘要

The fatty acid-binding protein 1 (FABP1) has drawn increasing attention as a promising target for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). However, efforts to validate pharmacological effects of FABP1 are restricted by the lack of relevant inhibitors. Herein, we identified the lead compound 1 with potent inhibition on FABP1 through screening from our in-house library. Further comprehensive structure-activity relationship (SAR) study based on compound 1 resulted in the identification of the optimal compound 12 (IC50 = 3.6 µM). Moreover, compound 12 exerted stronger efficacy on reducing hepatic lipid accumulation, inflammation and fibrosis than that of clinical candidate GFT505 in MASH models. In addition, compound 12 significantly inhibited fibrosis-related gene expression in TGF-β treated hepatic stellate cells and exerted stronger effects than Pirfenidone in CCl4-induced liver fibrosis mice model. These results indicated that compound 12 may serve as a novel FABP1 inhibitor for the treatment of MASH and liver fibrosis.