MTX115325 (Example 1) is a brain-penetrant USP30 inhibitor with an IC 50 of 12 nM, administered orally and exhibiting neuroprotective properties. It enhances ubiquitination (EC 50 =32 nM) of TOM20, a mitochondrial outer membrane protein and USP30 substrate, thereby promoting mitophagy. Additionally, MTX115325 prevents dopaminergic neuron loss and maintains striatal dopamine [1].

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

MTX115325, when administered intragastrically at doses of 15 mg/kg and 50 mg/kg twice daily for 10 weeks in the AAV-A53T-SNCA mouse model, reduces phosphorylated S129-αSyn levels and decreases the total area of GFAP staining, indicating reduced astrocyte activation [1]. As a single dose, MTX115325 at 10 mg/kg demonstrates excellent oral bioavailability (98%) and good central nervous system penetration, with a brain distribution coefficient (Kpu, u) of approximately 0.4 [1]. The Cmax of MTX115325 at a single dose is 7546.9 ng/mL for 15 mg/kg and 16374.3 ng/mL for 50 mg/kg, with drug concentrations consistently surpassing the EC50 for TOM20 ubiquitination at the 50 mg/kg dose [1]. In the AAV-A53T-SNCA Mouse Model [1], MTX115325 at dosages of 15 mg/kg and 50 mg/kg, administered intragastrically twice daily for 10 weeks, significantly reduces the loss of dopaminergic neurons in the substantia nigra (SN) and preserves dopamine levels in the striatum, while also increasing the percentage of tyrosine hydroxylase (TH)+ neurons.