2. Academic Validation
  3. Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease

Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease

  • Acta Pharmacol Sin. 2025 Mar 11. doi: 10.1038/s41401-025-01525-7.
Wen-Sheng Yang # 1,  Qing Liu # 2,  Yang Li 3,  Guan-Yi Li 4,  Shi Lin 5,  Jie Li 3,  Lin-Yu Li 1,  Yuan Li 5,  Xi-Lin Ge 1,  Xiao-Zhen Wang 5,  Wei Wu 1,  Jun Yan 6,  Guang-Fei Wang 1,  Qing-Tong Zhou 3 5 7,  Qiang Liu 8,  Ming-Wei Wang 9 10 11,  Zhi-Ping Li 12 13
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China.
  • 2 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
  • 4 School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 5 Research Center for Deepsea Bioresources, Sanya, 572025, China.
  • 6 Department of Laboratory Animal Science, Fudan University, Shanghai, 200032, China.
  • 7 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 8 Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
  • 9 Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. mwwang@simm.ac.cn.
  • 10 Research Center for Deepsea Bioresources, Sanya, 572025, China. mwwang@simm.ac.cn.
  • 11 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. mwwang@simm.ac.cn.
  • 12 Department of Clinical Pharmacy, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China. zpli@fudan.edu.cn.
  • 13 Department of Clinical Pharmacy, Kunshan Maternity and Children's Health Care Hospital, Children's Hospital of Fudan University Kunshan Branch, Kunshan, 215300, China. zpli@fudan.edu.cn.
  • # Contributed equally.
PMID: 40069490 DOI: 10.1038/s41401-025-01525-7
Abstract

Current treatments of inflammatory bowel disease (IBD) largely depend on anti-inflammatory and immunosuppressive strategies with unacceptable efficacy and adverse events. Resolution or repair agents to treat IBD are not available but potential targets like formyl peptide receptor 2 (FPR2/ALX) may fill the gap. In this study we evaluated the therapeutic effects of two small molecule FPR2/ALX modulators (agonist Quin-C1 and antagonist Quin-C7) against IBD. We first analyzed the cryo-electron microscopy structure of the Quin-C1-FPR2 in complex with heterotrimeric Gi to reveal the structural basis for ligand recognition and FPR2 activation. We then established dextran sulfate sodium (DSS)-induced colitis model in both normal and myeloid depletion mice. We showed that oral administration of Quin-C1 for 7 days ameliorated DSS-induced colitis evidenced by alleviated disease activity indexes, reduced colonic histopathological scores, and corrected cytokine disorders. Meanwhile, we found that oral administration of FPR2/ALX antagonist Quin-C7 exerted therapeutic actions similar to those of Quin-C1. In terms of symptomatic improvements, the ED50 values of Quin-C1 and Quin-C7 were 1.3660 mg/kg and 2.2110 mg/kg, respectively. The underlying mechanisms involved ERK- or ERK/JNK-mediated myeloid cell regulation that limited the development of colitis and inflammation. This is the first demonstration of anti-colitis property caused by synthetic small molecule FPR2/ALX modulators, implying that FPR2/ALX modulation rather than agonism alone ameliorates IBD.

Keywords

FPR2/ALX; IBD; Quin-C1; Quin-C7; macrophages; neutrophils.

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