6RFJ

IRAK4 IN COMPLEX WITH inhibitor

Summary for 6RFJ

• Entry DOI: 10.2210/pdb6rfj/pdb
• Descriptor: Interleukin-1 receptor-associated kinase 4, methyl 4-[4-[[6-(cyanomethyl)-2-[(1-methylpyrazol-4-yl)amino]pyrido[3,2-d]pyrimidin-4-yl]amino]cyclohexyl]piperazine-1-carboxylate, SULFATE ION, ... (4 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: 74161.40

Authors

Xue, Y.,Degorce, S.L.,Robb, G.R.,Ferguson, A.D. (deposition date: 2019-04-15, release date: 2019-10-30, Last modification date: 2024-10-23)

Primary citation

Degorce, S.L.,Anjum, R.,Bloecher, A.,Carbajo, R.J.,Dillman, K.S.,Drew, L.,Halsall, C.T.,Lenz, E.M.,Lindsay, N.A.,Mayo, M.F.,Pink, J.H.,Robb, G.R.,Rosen, A.,Scott, J.S.,Xue, Y.
Discovery of a Series of 5-Azaquinazolines as Orally Efficacious IRAK4 Inhibitors Targeting MyD88L265PMutant Diffuse Large B Cell Lymphoma.
J.Med.Chem., 62:9918-9930, 2019

PubMed Abstract: In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline , we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline , a selective IRAK4 inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of toward IRAK4.

PubMed: 31622099
DOI: 10.1021/acs.jmedchem.9b01346

Experimental method

X-RAY DIFFRACTION (2.61 Å)