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ID: ALA4024763
Journal: J Med Chem
Title: 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.
Authors: Scott JS, Degorce SL, Anjum R, Culshaw J, Davies RDM, Davies NL, Dillman KS, Dowling JE, Drew L, Ferguson AD, Groombridge SD, Halsall CT, Hudson JA, Lamont S, Lindsay NA, Marden SK, Mayo MF, Pease JE, Perkins DR, Pink JH, Robb GR, Rosen A, Shen M, McWhirter C, Wu D.
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.
CiteXplore: 29172502