Abstract
In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, 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 13, 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 13 toward IRAK4.
MeSH terms
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Administration, Oral
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Animals
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Cell Line, Tumor
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Drug Design
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Female
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Humans
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Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
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Interleukin-1 Receptor-Associated Kinases / chemistry
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Lymphoma, Large B-Cell, Diffuse / drug therapy*
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / pathology
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Mice
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Models, Molecular
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Molecular Targeted Therapy*
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Mutation
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Myeloid Differentiation Factor 88 / genetics*
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Protein Conformation
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Quinazolines / administration & dosage
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Quinazolines / chemistry*
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Quinazolines / pharmacokinetics
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Quinazolines / pharmacology*
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Rats
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Rats, Wistar
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Structure-Activity Relationship
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Tissue Distribution
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Xenograft Model Antitumor Assays
Substances
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Myeloid Differentiation Factor 88
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Protein Kinase Inhibitors
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Quinazolines
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IRAK4 protein, human
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Interleukin-1 Receptor-Associated Kinases