4‑Anilinoquinazoline\nDerivatives as the First\nPotent NOD1-RIPK2 Signaling Pathway Inhibitors at the Nanomolar Range

Inflammation is a defense mechanism that restores tissue\ndamage\nand eliminates pathogens. Among the pattern recognition receptors\nthat recognize danger or pathogenic signals, nucleotide oligomerization\ndomains 1 and 2 (NOD1/2) have been identified to play an important\nrole in innate immunity responses, and inhibition of NOD1 could be\ninteresting to treat severe infections and inflammatory diseases.\nIn this work, we identified the first selective NOD1 versus NOD2 pathway\ninhibitors at the nanomolar range based on a 4-anilinoquinazoline\nscaffold. We demonstrated that NOD1 inhibition occurs through the\ninhibition of receptor interacting protein kinase 2 (RIPK2), which\nis involved in its downstream signaling pathways. Compound <b>37</b> demonstrates no cytotoxicity, a selectivity for RIPK2 over epithelial\nand vascular endothelial growth factor receptors (EGFR/VEGFR), and\na capacity to reduce pro-inflammatory cytokine IL-8 secretion. The\nstructure of the RIPK2–compound <b>37</b> complex was\nresolved by crystallography. The 4-anilinoquinazoline scaffold offers\nnovel perspectives to design NOD1-RIPK2 signaling inhibitors.