Discovery of c-Kit as a New Therapeutic Target in LPS-Induced Acute Lung Injury through Novel Phenylamide Derivative D9

  • J Med Chem. 2025 Apr 10;68(7):7499-7517. doi: 10.1021/acs.jmedchem.4c03229.
Wu Luo  1 ,  Ke Dong  1  2 ,  Jintian Dai  1  2 ,  Anqi Zhang  1 ,  Pan Chen  1 ,  Zhichao Chen  1 ,  Mi Guo  1 ,  Chenhui Sun  2 ,  Jun Yang  1 ,  Nan Huang  1 ,  Yu Zou  1 ,  Zhiwei Zheng  1 ,  Won-Jea Cho  3 ,  Xiaojun Chen  4 ,  Young-Chang Cho  3 ,  Jinfeng Sun  5 ,  Guang Liang  1  6  2 ,  Qidong Tang  1  5  2
Affiliations
  • 1. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 2. Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China.
  • 3. College of Pharmacy, Chonnam National University, Gwangju 61186, South Korea.
  • 4. Department of Pharmacy, Wenzhou Nursing School, Wenzhou, Zhejiang 325000, China.
  • 5. Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University College of Pharmacy, Yanji, Jilin 133002, China.
  • 6. School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China.
PMID: 40125948 DOI: 10.1021/acs.jmedchem.4c03229
Abstract

Discovering effective anti-inflammatory drugs and targets is a critical research priority. Herein, 28 novel phenylamide derivatives were designed and synthesized. Compound D9 showed favorable anti-inflammatory activities in acute lung injury (ALI) and sepsis mouse models. The target of D9 was predicted and studied, and c-Kit was identified by surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA), which demonstrated high selectivity in kinase activity profiling. It was further verified that c-Kit participated in the LPS-induced inflammatory response in J774A.1, RAW264.7, MPMs, and lung tissue. Additionally, c-Kit is proved to be essential for LPS-induced activation of the NF-κB pathway. Finally, c-Kit was confirmed as a therapeutic target in the LPS-induced ALI with c-Kit gene knockdown and was further verified as the target of D9. Notably, there has been no report of c-Kit's influence on the LPS-induced inflammatory response. Therefore, c-Kit was identified as a new therapeutic target for the LPS-induced ALI.

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