title: Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy.
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.
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Priscilla N
authors.initials: PN
authors.lastname: Kelly
authors.affiliation: Nimbus Therapeutics, Cambridge, MA 02141.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Romero
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.affiliation: Nimbus Therapeutics, Cambridge, MA 02141.
authors.forename: Divya
authors.initials: D
authors.lastname: Chaudhary
authors.affiliation: Schrödinger, New York, NY 10036.
authors.forename: Shaughnessy
authors.initials: S
authors.lastname: Robinson
authors.affiliation: Nimbus Therapeutics, Cambridge, MA 02141.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Miao
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Lixin
authors.initials: L
authors.lastname: Rui
authors.affiliation: Nimbus Therapeutics, Cambridge, MA 02141.
authors.forename: William F
authors.initials: WF
authors.lastname: Westlin
authors.affiliation: Nimbus Therapeutics, Cambridge, MA 02141.
authors.forename: Rosana
authors.initials: R
authors.lastname: Kapeller
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 lstaudt@mail.nih.gov.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D055808:Drug Discovery; D006073:Gout / Q000188:drug therapy; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D053594:Myeloid Differentiation Factor 88; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases