2. Academic Validation
  3. Fragment-Based Anti-inflammatory Agent Design and Target Identification: Discovery of AF-45 as an IRAK4 Inhibitor to Treat Ulcerative Colitis and Acute Lung Injury

Fragment-Based Anti-inflammatory Agent Design and Target Identification: Discovery of AF-45 as an IRAK4 Inhibitor to Treat Ulcerative Colitis and Acute Lung Injury

  • J Med Chem. 2024 Jun 24. doi: 10.1021/acs.jmedchem.4c00202.
Yu Zou 1 2,  Xiemin Wang 1 2,  Pan Chen 1 2 3,  Zhiwei Zheng 1 2 4,  Xiaobo Li 1 2,  Zhichao Chen 1 2,  Mi Guo 1 2,  Ying Zhou 1 2,  Chenhui Sun 1 2,  Ran Wang 5,  Wufu Zhu 5,  Pengwu Zheng 5,  Won-Jea Cho 4,  Young-Chang Cho 4,  Guang Liang 1 6 2 3,  Qidong Tang 1 2
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 2 Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325024, China.
  • 3 Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
  • 4 College of Pharmacy, Chonnam National University, Gwangju 61186, Korea.
  • 5 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China.
  • 6 School of Pharmacy, Hangzhou Medical College, Hangzhou 311399, China.
PMID: 38913701 DOI: 10.1021/acs.jmedchem.4c00202
Abstract

UC and ALI are inflammatory diseases with limited treatment in the clinic. Herein, fragment-based anti-inflammatory agent designs were carried out deriving from cyclohexylamine/cyclobutylamine and several fragments from anti-inflammatory agents in our lab. AF-45 (IC50 = 0.53/0.60 μM on IL-6/TNF-α in THP-1 macrophages) was identified as the optimal molecule using ELISA and MTT assays from the 33 synthesized compounds. Through mechanistic studies and a systematic target search process, AF-45 was found to block the NF-κB/MAPK pathway and target IRAK4, a promising target for inflammation and autoimmune diseases. The selectivity of AF-45 targeting IRAK4 was validated by comparing its effects on other kinase/nonkinase proteins. In vivo, AF-45 exhibited a good therapeutic effect on UC and ALI, and favorable PK proprieties. Since there are currently no clinical or preclinical trials for IRAK4 inhibitors to treat UC and ALI, AF-45 provides a new lead compound or candidate targeting IRAK4 for the treatment of these diseases.

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