Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell Lymphoma
2017
Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of
interleukin-1 receptorassociated 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
IRAK4inhibition 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
ibrutinibled to tumor regression in an ABC-DLBCL mouse model.
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