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Description: IU1 (IU-1; IU 1) is a cell-permeable, reversible and selective proteasome inhibitor of human USP14 with the potential to be used for treating neurodegenerative disease. It inhibits USP14 with an IC50 of 4.7 u M, and shows 25-fold higher selectivity against IsoT. USP14 is a proteasome-associated deubiquitinating enzyme that can inhibit the degradation of ubiquitin-protein conjugates both in vitro and in cells. IU1 prevents ventilator-induced lung injury in rats and can inhibit the catalytic activity of proteasome-associated USP14 in vitro with IC50 < 4 uM. Treatment of cultured cells with IU1 enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. USP14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress. Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress.
References: Nature. 2010 Sep 9; 467(7312): 179–184.
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