9F3V
RIP2K kinase domain dimer with bound compound 37 (N399), a speific NOD1 pathway inhibitor
This is a non-PDB format compatible entry.
Summary for 9F3V
Entry DOI | 10.2210/pdb9f3v/pdb |
Descriptor | Receptor-interacting serine/threonine-protein kinase 2, N-[2,4-bis(chloranyl)-5-methoxy-phenyl]-7-[2-(diethylamino)ethoxy]-6-methoxy-quinazolin-4-amine (3 entities in total) |
Functional Keywords | kinase, immune system |
Biological source | Homo sapiens (human) |
Total number of polymer chains | 2 |
Total formula weight | 74219.06 |
Authors | |
Primary citation | Barczyk, A.,Six, P.,Rivoal, M.,Devos, C.,Dezitter, X.,Cornu-Choi, M.J.,Huard, K.,Pellegrini, E.,Cusack, S.,Dubuquoy, L.,Millet, R.,Leleu-Chavain, N. 4-Anilinoquinazoline Derivatives as the First Potent NOD1-RIPK2 Signaling Pathway Inhibitors at the Nanomolar Range. J.Med.Chem., 2024 Cited by PubMed Abstract: Inflammation is a defense mechanism that restores tissue damage and eliminates pathogens. Among the pattern recognition receptors that recognize danger or pathogenic signals, nucleotide oligomerization domains 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 versus 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), which is involved in its downstream signaling pathways. Compound 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 complex was resolved by crystallography. The 4-anilinoquinazoline scaffold offers novel perspectives to design NOD1-RIPK2 signaling inhibitors. PubMed: 39444201DOI: 10.1021/acs.jmedchem.4c01713 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.943 Å) |
Structure validation
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