PYR-41 is the first cell-permeable inhibitor of ubiquitin-activating enzyme E1, with no activity at E2.PYR-41 (50 M) inhibits activity of ubiquitin-activating enzyme E1 by over 90%. PYR-41 could be a target for nucleophilic attack and potentially reacts with the active site cysteine of E1. PYR-41 efficiently blocks cyclin E degradation. PYR-41 decreases the level of E1fUb thioesters in cells with a IC50 of between 10 and 25 M, and prevents proteasome inhibitorCinduced accumulation of ubiquitylated proteins. PYR-41 increases total sumoylation in cells and in cell harboring temperature-sensitive E1. PYR-41 is able to inhibit both proteasome-dependent and proteasome-independent activities of ubiquitylation. PYR-41 (50 M) attenuates 1 ng/mL IL-1-mediated nuclear factor-B activation by >60% through preventing the downstream ubiquitylation and proteasomal degradation of IB. PYR-41 inhibits degradation of p53 and activates the transcriptional activity of p53, which enable its differentially killing transformed p53-expressing cells
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