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Series GSE63029 Query DataSets for GSE63029
Status Public on Nov 01, 2015
Title Highly Potent and Selective Interleukin-1 Receptor-Associated Kinase 4 Inhibitors for the Treatment of Lymphoid Malignancies
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapeutics tailored to disease-causing mechanisms are needed. Pivotal to TLR signaling is the IL-1 receptor-associated kinase 4 (IRAK4), which is recruited to TLRs by the adaptor protein MyD88. Recruitment of IRAK kinases to MyD88, triggers the formation of a signaling competent myddosome complex, which underlies the pathogenesis of many immuno-inflammatory disorders, suggesting that IRAK4 inhibitors might be useful in the treatment of these diseases. Gain-of-function MYD88 mutations activate IRAK4 in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 inhibitors has been confounded by the challenging structure of the IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 inhibitors. These small molecules suppress LPS-induced TNFalpha production in vitro and in vivo, and are efficacious in mouse models of collagen-induced arthritis and MyD88-dependent inflammatory gout. Human ABC DLBCL cell lines that harbor the activating, oncogenic MyD88 L265P mutation are killed by IRAK4 inhibitors, both in vitro and in mouse xenograft models. IRAK4 inhibitors synergize with the BTK inhibitor ibrutinib, with the Syk inhibitor PRT062607, and with the Bcl-2 inhibitor ABT-199 in killing ABC DLBCL cells, suggesting new therapeutic strategies for this refractory cancer.
Overall design Four ABC DLBCL cell lines (OCI-Ly10, TMD8, HBL1 and OCI-Ly3), were treated with either ND-2158 or the structurally related negative control compound ND-1659 for 6, 12, 24 or 36 h in culture. Gene expression profiling was performed using two-color human Agilent 4x44K gene expression arrays comparing signal from control compound-treated (ND-1659) control cells (Cy3), to cells treated with ND-2158 for the indicated times (Cy5).
Citation(s) 26621451
Submission date Nov 06, 2014
Last update date Feb 22, 2018
Contact name Louis M. Staudt
Phone 301-402-1892
Organization name National Cancer Institute
Department Lymphoid Malignancies Branch
Lab Louis M Staudt
Street address 9000 Rockville Pike, Bldg 10, Rm 4N114
City Bethesda
State/province MD
ZIP/Postal code 20892
Country USA
Platforms (1)
GPL4133 Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version)
Samples (16)
GSM1538328 TMD8 ND-2158 vs ND-1659 - 6 hours - mAdbID:125690
GSM1538329 TMD8 ND-2158 vs ND-1659 - 12 hours - mAdbID:125691
GSM1538330 TMD8 ND-2158 vs ND-1659 - 24 hours - mAdbID:125692
BioProject PRJNA266478

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Supplementary file Size Download File type/resource
GSE63029_RAW.tar 252.3 Mb (http)(custom) TAR (of TXT)
Processed data included within Sample table

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