2. Academic Validation
  3. Discovery of the first-in-class FABP/PPAR multiple modulator for the treatment of metabolic dysfunction-associated steatohepatitis

Discovery of the first-in-class FABP/PPAR multiple modulator for the treatment of metabolic dysfunction-associated steatohepatitis

  • Eur J Med Chem. 2025 Jul 5:291:117635. doi: 10.1016/j.ejmech.2025.117635.
Ya Chen 1,  Zibin Liao 1,  Jianming Mao 1,  Wenxin Wang 1,  Yuxia Liu 1,  Wei Dai 2,  Zheng Wen 3,  Sishi Liu 4,  Yayi Chen 1,  Yiming Ma 1,  Xiaoying Wang 5,  Zheng Li 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
  • 2 Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, PR China.
  • 3 Department of Emergency, Baiyun Hospital of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510000, PR China.
  • 4 Department of Gynecology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China.
  • 5 Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, PR China. Electronic address: wxying@mail.sysu.edu.cn.
  • 6 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China. Electronic address: lizhengdrug@gdpu.edu.cn.
PMID: 40279770 DOI: 10.1016/j.ejmech.2025.117635
Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a complex metabolic syndrome, and the development of new drugs is urgently needed. Fatty acid binding proteins (FABPs) and peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of lipid absorption, metabolism and inflammation. Considering the synergistic effect of FABP and PPAR in the regulation of MASH pathophysiology, the development of FABP/PPAR multiple modulators might be a promising anti-MASH strategy. Herein, the first-in-class FABP/PPAR multiple modulators were designed by hybrid resveratrol and PPARs agonist Elafibranor. Among them, the compound 27 was identified as the optimal FABP/PPAR multiple modulator (FABP1 IC50 = 0.65 μM, FABP4 IC50 = 1.08 μM, PPARα EC50 = 9.19 μM, PPARγ EC50 = 2.20 μM, PPARδ EC50 = 1.58 μM). Further MST assay confirmed the direct interaction of compound 27 and FABP1, providing a robust validation of its target specificity. In MASH mice, compound 27 exhibited a better therapeutic effect than clinical candidate obeticholic acid in ameliorating multiple pathological features of MASH. This study reported the successful discovery of the first-in-class FABP/PPAR multiple modulators, which provided preliminary evidence that such multi-target agents have broad medical prospects.

Keywords

FABP1; FABP4; Fibrosis; Inflammation; MASH; PPARs.

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