Discovery of c-Kit as a New Therapeutic Target in LPS-Induced Acute Lung Injury through Novel Phenylamide Derivative D9
Discovering effective anti-inflammatory drugs and targets is a critical research priority. Herein, 28 novel phenylamide derivatives were designed and synthesized. Compound <b>D9</b> showed favorable anti-inflammatory activities in acute lung injury (ALI) and sepsis mouse models. The target of <b>D9</b> 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 <b>D9</b>. 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.
Authors
- Jintian Dai
- Qidong Tang (ORCID: https://orcid.org/0000-0002-2045-4646)
- Ke Dong (ORCID: https://orcid.org/0000-0002-9773-6350)
- Jinfeng Sun (ORCID: https://orcid.org/0000-0002-5576-1654)
- Won-Jea Cho
- Young-Chang Cho (ORCID: https://orcid.org/0000-0003-3227-579X)
- Wu Luo
- Nan Huang (ORCID: https://orcid.org/0000-0001-6811-0810)
- Anqi Zhang (ORCID: https://orcid.org/0000-0003-0142-0106)
- Xiaojun Chen (ORCID: https://orcid.org/0000-0002-6835-2913)
- Pan Chen (ORCID: https://orcid.org/0009-0009-7507-3398)
- Zhichao Chen (ORCID: https://orcid.org/0000-0003-2311-4345)
- Mi Guo
- Yu Zou
- Jun Yang (ORCID: https://orcid.org/0000-0002-0080-0476)
- Chenhui Sun
- Zhiwei Zheng
- Guang Liang (ORCID: https://orcid.org/0009-0005-1603-3223)
Institutions
- Wenzhou University (CN)
- Yanbian University (CN)
- Wenzhou Medical University (CN)
- Chonnam National University Hospital (KR)
- University of Chinese Academy of Sciences (CN)
- Hangzhou Medical College (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-24
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03229
- Citations
- 4
- Primary Topic
- Neonatal Respiratory Health Research
- Type
- article
- Field-Weighted Citation Impact
- 6.07
Funders
- Wenzhou Medical University
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- University of Chinese Academy of Sciences