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

  • J Med Chem. 2017 Dec 28;60(24):10071-10091. doi: 10.1021/acs.jmedchem.7b01290.
James S Scott  1 ,  Sébastien L Degorce  1 ,  Rana Anjum  2 ,  Janet Culshaw  3 ,  Robert D M Davies  3 ,  Nichola L Davies  1 ,  Keith S Dillman  2 ,  James E Dowling  2 ,  Lisa Drew  2 ,  Andrew D Ferguson  2 ,  Sam D Groombridge  3 ,  Christopher T Halsall  3 ,  Julian A Hudson  3 ,  Scott Lamont  1 ,  Nicola A Lindsay  1 ,  Stacey K Marden  4 ,  Michele F Mayo  2 ,  J Elizabeth Pease  1 ,  David R Perkins  3 ,  Jennifer H Pink  3 ,  Graeme R Robb  1 ,  Alan Rosen  2 ,  Minhui Shen  2 ,  Claire McWhirter  1 ,  Dedong Wu  4
Affiliations
  • 1. Oncology, IMED Biotech Unit, AstraZeneca , Cambridge CB4 0FZ, United Kingdom.
  • 2. Oncology, IMED Biotech Unit, AstraZeneca , Boston, Massachusetts 02451, United States.
  • 3. Oncology, IMED Biotech Unit, AstraZeneca , Macclesfield SK10 4TG, United Kingdom.
  • 4. Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca , Boston, Massachusetts 02451, United States.
PMID: 29172502 DOI: 10.1021/acs.jmedchem.7b01290
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.

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