Luo Wu, Dong Ke, Dai Jintian, Zhang Anqi, Chen Pan, Chen Zhichao, Guo Mi, Sun Chenhui, Yang Jun, Huang Nan, Zou Yu, Zheng Zhiwei, Cho Won-Jea, Chen Xiaojun, Cho Young-Chang, Sun Jinfeng, Liang Guang, Tang Qidong
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China.
J Med Chem. 2025 Apr 10;68(7):7499-7517. doi: 10.1021/acs.jmedchem.4c03229. Epub 2025 Mar 24.
Discovering effective anti-inflammatory drugs and targets is a critical research priority. Herein, 28 novel phenylamide derivatives were designed and synthesized. Compound showed favorable anti-inflammatory activities in acute lung injury (ALI) and sepsis mouse models. The target of 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 . 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.
发现有效的抗炎药物和靶点是一项关键的研究重点。在此，设计并合成了28种新型苯酰胺衍生物。化合物在急性肺损伤（ALI）和脓毒症小鼠模型中表现出良好的抗炎活性。对其靶点进行了预测和研究，通过表面等离子体共振（SPR）和细胞热位移分析（CETSA）鉴定出c-Kit，其在激酶活性谱分析中显示出高选择性。进一步证实c-Kit参与了J774A.1、RAW264.7、MPMs和肺组织中LPS诱导的炎症反应。此外，证明c-Kit对于LPS诱导的NF-κB通路激活至关重要。最后，通过c-Kit基因敲低证实c-Kit是LPS诱导的ALI中的治疗靶点，并进一步验证其为该化合物的靶点。值得注意的是，尚无关于c-Kit对LPS诱导的炎症反应影响的报道。因此，c-Kit被确定为LPS诱导的ALI的新治疗靶点。
