@entity2451 -induced gene expression contributes significantly to the pathogenesis of @entity32 such as @entity625 . I kappa B kinase (IKK) is the converging point for the activation of @entity2451 by a broad spectrum of inflammatory agonists and is thus a novel target for therapeutic intervention. We describe a small molecule, selective inhibitor of @entity15955 , @entity53695 , which does not inhibit other IKK isoforms or other @entity563 - @entity1889 and @entity669 kinases. @entity53695 inhibits the native IKK complex or recombinant @entity1 @entity18159 / @entity15955 heterodimer and @entity15955 homodimer similarly. @entity15955 inhibition by @entity53695 is selective, reversible, and competitive with @entity855 . @entity53695 inhibits transcription of @entity2451 -dependent genes in @entity1356 -induced @entity309 -derived synovial fibroblasts in a dose-dependent manner. When the mechanism of @entity2451 activation was evaluated in the presence of this inhibitor, several interesting observations were found. First, @entity53695 did not inhibit the phosphorylation and activation of the IKK complex. Second, there was a delay but not a complete blockade in @entity4284 phosphorylation and degradation; likewise there was a slightly slowed, decreased import of @entity9135 into the nucleus and a faster export of @entity9135 from the nucleus. Finally, both @entity4284 and @entity9135 were comparable substrates for @entity15955 , with similar Km and Kcat values, and @entity53695 inhibited the phosphorylation of either substrate similarly. Thus, the effect of @entity53695 on cytokine gene expression may be a combination of inhibiting @entity4284 phosphorylation/degradation, affecting @entity2451 nuclear import/export as well as the phosphorylation and transactivation of @entity9135 .

A selective @entity15955 inhibitor blocks @entity2451 -dependent gene expression in XXXX -stimulated synovial fibroblasts.

@entity1 :: ('9606', 'Species') :: ['human'] @entity32 :: ('MESH:D007249', 'Disease') :: ['inflammatory diseases'] @entity9135 :: ('5970', 'Gene') :: ['p65'] @entity2451 :: ('4790', 'Gene') :: ['NF-kappa B'] @entity625 :: ('MESH:D001168', 'Disease') :: ['arthritis'] @entity1356 :: ('3553', 'Gene') :: ['IL-1 beta'] @entity15955 :: ('3551', 'Gene') :: ['IKK-2'] @entity4284 :: ('4792', 'Gene') :: ['I kappa B alpha'] @entity53695 :: ('MESH:C477523', 'Chemical') :: ['SC-514'] @entity18159 :: ('1147', 'Gene') :: ['IKK-1'] @entity563 :: ('CHEBI:17822', 'Chemical') :: ['serine'] @entity1889 :: ('CHEBI:26986', 'Chemical') :: ['threonine'] @entity669 :: ('CHEBI:18186', 'Chemical') :: ['tyrosine'] @entity309 :: ('MESH:D001172', 'Disease') :: ['rheumatoid arthritis'] @entity855 :: ('MESH:D000255', 'Chemical') :: ['ATP']
@entity1356 :: (3553,Gene) :: ['interleukin-1 beta']
