Design, synthesis, and biological evaluation of novel discoidin domain receptor inhibitors for the treatment of lung adenocarcinoma and pulmonary fibrosis.

Discoidin domain receptors (DDR) play crucial roles in cell proliferation and differentiation. When DDRs are overexpressed, it has been associated with various diseases such as cancers, fibrotic disorders, and inflammation. This study aimed to expand on previous research by using a structure-based drug design approach to develop a series of new indole-urea derivatives as potent inhibitors of DDR1. Through biochemical analyses, it was found that these compounds effectively inhibited DDR1/2, with compound 7s demonstrating the highest activity against A549 cells (IC50 value of 1.84 μM) while maintaining selectivity for other kinases. In vivo studies showed that compound 7s exhibited stronger antitumor activity compared to dasatinib, without causing significant weight loss at a dose of 30 mg/kg. Further investigation revealed that compound 7s hindered the migration of A549 cells by targeting the ERK, Akt1, and EMT pathways. Additionally, cellular experiments demonstrated that compound 7s suppressed the activation of fibroblasts induced by TGF-β1. In vivo experiments confirmed that compound 7s, at a dose of 30 mg/kg, effectively inhibited DDR1 activation, resulting in a reduction of lung injury and fibrosis induced by bleomycin. Overall, these findings highlight the potential of these novel DDR1 inhibitors as promising therapeutic candidates for the treatment of DDR-related diseases.