USP14 Inhibitor, IU1

A cell-permeable pyrrolylpyrrolidinyl-ethanone that inhibits the proteasome association-dependent USP14 deubiquitinase (DUB) activity in a reversible manner (IC₅₀ = 4.7 M against Ub-AMC hydrolysis), likely by targeting USP14 active site thiol, while exhibiting little or no activity toward 8 other DUBs (<10% inhibition of IsoT, UCH37/UCH-L5, BAP1, UCH-L1, UCH-L3, USP2, USP7, and USP15 at 17 M). Shown to downregulate tau, TDP-43, ATXN3, GFAP, and free Ub levels in MEF cultures in a dose- (25 to 100 M), time-, and USP14-dependent manner. Effectively protects HEK293 cells from menadione toxicity (90% vs. 40% viability after 4 h 100 M menadione treatment, respectively, with or without 50 M IU1 pretreatment) by reducing the built-up of oxidized proteins. USP14-catalyzed trimming of protein surface polyubiquitin chains rescues proteasome-bound proteins from proteolytic degradation and thereby prevents the depletion of free ubiquitin pool in cells. Comparing to b-AP15 (Cat. No. 662140), IU1 does not inhibit UCH37/UCH-L5 (IC₅₀ = 700 M).

A cell-permeable pyrrolylpyrrolidinyl-ethanone that inhibits the proteasome association-dependent USP14 deubiquitinase (DUB) activity in a reversible manner (IC₅₀ = 4.7 µM against Ub-AMC hydrolysis), exhibiting little or no activity toward 8 other DUBs. Shown to downregulate tau, TDP-43, ATXN3, GFAP, and free Ub levels in MEF cultures in a dose- (25 to 100 µM), time-, and USP14-dependent manner. USP14-catalyzed trimming of protein surface polyubiquitin chains rescues proteasome-bound proteins from proteolytic degradation and thereby prevents the depletion of free ubiquitin pool in cells. Comparing to b-AP15 (Cat. No. 662140), IU1 does not inhibit UCH37/UCH-L5 (IC₅₀ = 700 µM).

Packaged under inert gas

Toxicity: Regulatory Review (Z)

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Lee, B.H., et al. 2010. Nature467, 179.

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