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
  • 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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