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IkappaB kinase (IKK) beta is essential for inflammatory cytokine-induced activation of nuclear factor kappaB (NF-kappaB). NF-kappaB plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA). Here, we report the mechanism and the effect of the IKKbeta inhibitor(More)
Constitutive activation of the NF-kappaB pathway is required for survival of the activated B cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL). Here we show that a small molecule IkappaB kinase (IKK) inhibitor, PS-1145, and related compounds are toxic for ABC DLBCL cell lines but not for cell lines derived from the other prevalent form of(More)
The transcription factor NF-kappaB plays a central role in regulating inflammation and apoptosis, making it a compelling target for drug development. We identified a small molecule inhibitor (ML120B) that specifically inhibits IKKbeta, an Ikappa-B kinase that regulates NF-kappaB. IKKbeta and NF-kappaB are required in vivo for prevention of TNFalpha-mediated(More)
OBJECTIVE The NF-kappaB signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF-kappaB activity is regulated by the IKK-2 kinase during inflammatory responses. To elucidate how IKK-2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and(More)
OBJECTIVE The IKK complex regulates NF-kappaB activation, an important pathway implicated in the rheumatoid arthritis (RA) disease process. This study was undertaken to assess the efficacy of N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a potent and selective small molecule inhibitor of IKKbeta. METHODS Polyarthritis was(More)
Neurofibrillary tangles in Alzheimer's disease contain aggregates of abnormally phosphorylated microtubule-associated protein tau, indicating that microtubule breakdown is a primary event in the neurodegenerative cascade. Recent studies have shown that addition to neuronal cultures of amyloid peptides found in Alzheimer's leads to abnormal phosphorylation(More)
The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38alpha. These efforts resulted in the identification of 12r and 19 as orally active(More)
A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the(More)
A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic(More)
SD0006 is a diarylpyrazole that was prepared as an inhibitor of p38 kinase-alpha (p38alpha). In vitro, SD0006 was selective for p38alpha kinase over 50 other kinases screened (including p38gamma and p38delta with modest selectivity over p38beta). Crystal structures with p38alpha show binding at the ATP site with additional residue interactions outside the(More)