6TIA

IRAK4 IN COMPLEX WITH inhibitor

Summary for 6TIA

• Entry DOI: 10.2210/pdb6tia/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, 4-(1-methylcyclopropyl)oxy-~{N}-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-6-(1-methylpyrazol-4-yl)pyrido[3,2-d]pyrimidin-2-amine (3 entities in total)
• Functional Keywords: irak4, kinase, inhibitor, cancer, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 73865.49

Authors

Xue, Y.,Aagaard, A.,Degorce, S.L. (deposition date: 2019-11-22, release date: 2020-10-28, Last modification date: 2024-05-01)

Primary citation

Degorce, S.L.,Aagaard, A.,Anjum, R.,Cumming, I.A.,Diene, C.R.,Fallan, C.,Johnson, T.,Leuchowius, K.J.,Orton, A.L.,Pearson, S.,Robb, G.R.,Rosen, A.,Scarfe, G.B.,Scott, J.S.,Smith, J.M.,Steward, O.R.,Terstiege, I.,Tucker, M.J.,Turner, P.,Wilkinson, S.D.,Wrigley, G.L.,Xue, Y.
Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors.
Bioorg.Med.Chem., 28:115815-115815, 2020

PubMed Abstract: In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib.

PubMed: 33091850
DOI: 10.1016/j.bmc.2020.115815

Experimental method

X-RAY DIFFRACTION (2.52 Å)