MTX115325

MTX115325 (Example 1) is an orally active, brain-penetrating USP30 inhibitor (IC50=12 nM) with neuroprotective activity. MTX115325 increases ubiquitination (EC50=32 nM) of the mitochondrial outer membrane protein TOM20 (a USP30 substrate), increasing mitophagy. MTX115325 prevents dopaminergic neuron loss and preserves striatal dopamine.

MTX115325 (37 nM-1 μM; 72 h) shows promotion of mitochondrial autophagy in SH-SY5Y cells^[1].
MTX115325 (10 nM-1 μM; 90 min) promotes ubiquitination of TOM20 and inhibits USP30 activity in both HeLa cells and YFP-Parkin overexpressing HeLa cells^[1].

MTX115325 (i.g.; 15 mg/kg and 50 mg/kg; twice daily for 10 weeks) reduces phosphorylated S129-αSyn levels and decreases the total area of GFAP staining in AAV-A53T-SNCA Mouse Model, indicating lower astrocyte activation^[1].
MTX115325 (i.g.; 10 mg/kg; single dose) demonstrates excellent oral bioavailability (98%) and good CNS penetration with a brain partition coefficient (Kpu,u) of approximately 0.4^[1].
MTX115325 (i.g.; single dose) has a C_max of 7546.9 ng/mL at 15 mg/kg and a C_max of 16374.3 ng/mL at 50 mg/kg. At a 50 mg/kg dosage, the drug concentration consistently remained above the EC₅₀ for TOM20 ubiquitination^[1].