Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy

J Exp Med. 2015 Dec 14;212(13):2189-201. doi: 10.1084/jem.20151074. Epub 2015 Nov 30.


Pathological activation of the Toll-like receptor signaling adaptor protein MYD88 underlies many autoimmune and inflammatory disease states. In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the oncogenic MYD88 L265P mutation occurs in 29% of cases, making it the most prevalent activating mutation in this malignancy. IRAK4 kinase accounts for almost all of the biological functions of MYD88, highlighting IRAK4 as a therapeutic target for diseases driven by aberrant MYD88 signaling. Using innovative structure-based drug design methodologies, we report the development of highly selective and bioavailable small molecule IRAK4 inhibitors, ND-2158 and ND-2110. These small molecules suppressed LPS-induced TNF production, alleviated collagen-induced arthritis, and blocked gout formation in mouse models. IRAK4 inhibition promoted killing of ABC DLBCL lines harboring MYD88 L265P, by down-modulating survival signals, including NF-κB and autocrine IL-6/IL-10 engagement of the JAK-STAT3 pathway. In ABC DLBCL xenograft models, IRAK4 inhibition suppressed tumor growth as a single agent, and in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib or the Bcl-2 inhibitor ABT-199. Our findings support pharmacological inhibition of IRAK4 as a therapeutic strategy in autoimmune disorders, in a genetically defined population of ABC DLBCL, and possibly other malignancies dependent on aberrant MYD88 signaling.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Arthritis, Experimental / drug therapy
  • Autoimmune Diseases / drug therapy*
  • Autoimmune Diseases / pathology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Drug Discovery
  • Gout / drug therapy
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred DBA
  • Myeloid Differentiation Factor 88 / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Antigen, B-Cell / metabolism
  • Signal Transduction / drug effects
  • Syk Kinase
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Intracellular Signaling Peptides and Proteins
  • Myeloid Differentiation Factor 88
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, B-Cell
  • Tumor Necrosis Factor-alpha
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Btk protein, mouse
  • SYK protein, human
  • Syk Kinase
  • Syk protein, mouse
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases