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

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 m...

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Bibliographic Details
Published in:The Journal of experimental medicine 2015-12, Vol.212 (13), p.2189-2201
Main Authors: Kelly, Priscilla N, Romero, Donna L, Yang, Yibin, Shaffer, 3rd, Arthur L, Chaudhary, Divya, Robinson, Shaughnessy, Miao, Wenyan, Rui, Lixin, Westlin, William F, Kapeller, Rosana, Staudt, Louis M
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20151074