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.
Priscilla N Kelly  1 ,  Donna L Romero  2 ,  Yibin Yang  1 ,  Arthur L Shaffer 3rd  1 ,  Divya Chaudhary  2 ,  Shaughnessy Robinson  3 ,  Wenyan Miao  2 ,  Lixin Rui  1 ,  William F Westlin  2 ,  Rosana Kapeller  2 ,  Louis M Staudt  4
Affiliations
  • 1. Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
  • 2. Nimbus Therapeutics, Cambridge, MA 02141.
  • 3. Schrödinger, New York, NY 10036.
  • 4. Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 [email protected].
PMID: 26621451 DOI: 10.1084/jem.20151074
Abstract

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.

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