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[1].
in vivo
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 Cmax of 7546.9 ng/mL at 15 mg/kg and a Cmax 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].
Animal Model:
AAV-A53T-SNCA Mouse Model [1]
Dosage:
15 mg/kg and 50 mg/kg
Administration:
i.g.; twice daily for 10 weeks
Result:
Reduced the loss of dopaminergic neurons in the substantia nigra (SN) and preserved dopamine levels in the striatum.
Increased the percentage of tyrosine hydroxylase (TH)+ neurons.
References
[1] Fang TZ et al. Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson's disease mouse model. Nat Commun. 2023 Nov 13;14(1):7295. DOI:10.1038/s41467-023-42876-1
