7qg3

IRAK4 in complex with inhibitor

spinqualitylabelsall models 7qg3, resolution 2.11Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.11Å Ligands: B4U, SEP, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group. Subsequent optimisation, facilitated by X-ray crystal structures, allowed identification of preferred substituents at both the pyridone core and pyrazole. Subsequent combinations of optimal groups allowed control of lipophilicity and identification of potent and selective inhibitors of IRAK4 with better in vitro permeability and lower clearance. Identification and optimisation of a pyrimidopyridone series of IRAK4 inhibitors.,Cumming IA, Degorce SL, Aagaard A, Braybrooke EL, Davies NL, Diene CR, Eatherton AJ, Felstead HR, Groombridge SD, Lenz EM, Li Y, Nai Y, Pearson S, Robb GR, Scott JS, Steward OR, Wu C, Xue Y, Zhang L, Zhang Y Bioorg Med Chem. 2022 Jun 1;63:116729. doi: 10.1016/j.bmc.2022.116729. Epub 2022 , Apr 2. PMID:35439688 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Interleukin-1 receptor-associated kinase

Proteopedia Page Contributors and Editors (what is this?)

OCA