Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88 L265P Diffuse Large B-Cell Lymphoma

J Med Chem. 2017 Dec 28;60(24):10071-10091. doi: 10.1021/acs.jmedchem.7b01290. Epub 2017 Dec 11.

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

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Dogs
  • Female
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
  • Interleukin-1 Receptor-Associated Kinases / chemistry
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice, SCID
  • Mutation
  • Myeloid Differentiation Factor 88 / genetics
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemistry
  • Pyrroles / chemistry
  • Rats, Wistar
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • pyrrolopyrimidine
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases