to thickening of the airway wall, leading to an amplification of bronchial hyperresponsiveness . Moreover, VEGF MCE Chemical NBI-56418 inhibition attenuates airway inflammation, AHR, and 1032350-13-2 peribronchial fibrosis . These findings suggest that an anti-inflammatory effect of IMD-4690 may result from VEGF suppression. To ensure that the decrease in Myc protein levels was selective and not a consequence of extensive protein degradation in the cell we monitored the levels of a number of other proteins, ranging in half life, in the Daudi and Raji cells after treatment with E08+N11 . The levels of these proteins are largely unaffected by E08+N11 treatment, other than a consistent modest decrease in protein levels at 24 hours post-treatment in the Daudi cells. This most likely correlates with the early onset of extensive apoptosis in this cell line in contrast to the Raji cells. Given that the primary role of Myc is to regulate gene expression, we next analyzed the effects of the dimeric inhibitors on a panel of Myc-dependent genes . We treated Daudi and Raji cells with the active dimer E08+N11 or its non-dimerizable control E08+C11 and analyzed gene expression using a panel of Myc-dependent genes 24 hours post-treatment. In both cell lines we observed a significant number of genes that were downregulated in response to E08+ N11 treatment but not E08+C11, consistent with Myc��s role as a transcriptional activator. A limited number of genes were upregulated in response to treatment but it was notable that in each cell line the cell cycle inhibitors CDKN2B or CDKN1B genes were upregulated by E08+ N11 but not E08+C11, consistent with the effects on cell viability in response to these treatments. Similar effects on Myc-dependent gene expression were observed with the dimeric inhibitor E07+N12 but not its non-dimerizable control E07+C12 . Notably the expression of Myc mRNA is decreased in response to E08+N11 in both the Daudi and Raji cells but not in the K562 cells , consistent with the effects on Myc steady state protein levels. This suggests that E08+N11 is not acting via a direct inhibition of Myc transcription but that the decrease in Myc mRNA is an indirect consequence of significant inhi
