IU1

IU1 is an inhibitor of USP14, a deubiquitinating enzyme associated with the proteasome. The proteasome mediates the cellular degradation of oxidized, damaged and misfolded proteins which, if not removed, accumulate and become toxic to cells. USP14 is one of several deubiquitinating enzymes (DUBs) responsible for shortening proteasome-bound ubiquitin chains, which is known to antagonize the degradation of ubiquitin-protein conjugates. IU1 inhibits the catalytic activity of proteasome-associated Usp14 in vitro (IC50 < 4 μM). IU1 selectively stimulates ubiquitin-dependent protein degradation in vitro at 34 μM and in MEF cells at 50 μM. At 75 μM, IU1 reduces accumulation of oxidized proteins in HEK293 cells, alleviating cytotoxicity induced by oxidative stress. IU1 may help to eliminate toxic proteins more effectively by enhancing their degradation.