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 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.