4-anilinoquinazoline derivatives as the first potent NOD1-RIPK2 signaling pathway inhibitors at the nanomolar range with potential anti-inflammatory activity

Inflammation is a defense mechanism that restores tissue damages and eliminates pathogens. Among the Pattern Recognition Receptors that recognize danger or pathogenic signals, Nucleotide Oligomerization Domain 1 and 2 (NOD1/2) have been identified to play an important role in innate immunity responses and inhibition of NOD1 could be interesting to treat severe infections and inflammatory diseases. In this work, we identified the first selective NOD1 vs NOD2 pathway inhibitors at the nanomolar range based on a 4-anilinoquinazoline scaffold. We demonstrated that NOD1 inhibition occurs through the inhibition of Receptor Interacting Protein Kinase 2 (RIPK2), involved in its downstream signaling pathways. Compound 37 demonstrates no cytotoxicity, a selectivity for RIPK2 over Epithelial and Vascular Endothelial Growth Factor Receptors (EGFR/VEGFR) and a capacity to reduce pro-inflammatory cytokine IL-8 secretion. The structure of the RIPK2-compound 37 complex was resolved by crystallography. The 4-anilinoquinazoline scaffold offers novel perspectives to design NOD1-RIPK2 inhibitors, potentially useful to treat inflammatory diseases.