MTX115325 (MTX325, MTX-325) is a potent, selective, brain-penetrant USP30 inhibitor with IC50 of 12 nM in biochemical fluorescence polarization assays.
MTX115325 exhibits high selectivity (>2000-fold) against 54 DUBs and other cysteinyl proteases.
MTX115325 blocks access of a ubiquitin-like probe to the enzyme active site in cells with IC50 of 25 nM.
MTX115325 increases ubiquitylation of the outer mitochondrial membrane protein TOM20, a USP30 substrate, with an EC1.5x and EC50 of 10 nM and 32 nM respectively, in human HeLa cell line overexpressing PARKIN and challenged with the mitochondrial toxins antimycin A and oligomycin A (A/O).
MTX115325 treatment (10 nM-1 uM) causes the upregulation of TOM20-ubiquitylation in human dopaminergic neurons in vitro, without any exogenous stimuli.
MTX115325 potently inhibits mouse USP30 with an IC50 of 13 nM, similar to human USP30.
MTX115325 (50 mg/kg BID, oral gavage) prevents dopaminergic neuronal loss and dopamine depletion in an α-synuclein-based PD mouse model.
MTX115325 recapitulates the effects of Usp30 KO in protecting against TH+ neuronal loss and striatal dopamine loss in an αSyn-based PD mouse model.