Abstract
Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Crystallography, X-Ray
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Dogs
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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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Magnetic Resonance Spectroscopy
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Male
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Mice, SCID
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Mutation
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Myeloid Differentiation Factor 88 / genetics
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Pyrimidines / chemistry
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Pyrroles / chemistry
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Rats, Wistar
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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MYD88 protein, human
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Myeloid Differentiation Factor 88
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Protein Kinase Inhibitors
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Pyrimidines
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Pyrroles
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pyrrolopyrimidine
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IRAK4 protein, human
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Interleukin-1 Receptor-Associated Kinases