Discovery and Development of USP30 inhibitors as Disease-Modifying Therapy for Parkinson's disease.

PROJECT SUMMARY/ABSTRACTThe proposed Phase I research is designed to establish the technical/scientific merit and feasibility of
developing first/best-in-class, USP30 inhibitors for the treatment of Parkinson’s disease (PD), an age-
associated neurodegenerative disorder second only to Alzheimer’s disease (AD) in prevalence. No therapy
that can slow or stop the progression of PD currently exists. Instead, treatments for PD, which affects 10
million people worldwide, merely augment dopaminergic neurotransmission to provide symptomatic benefit.
To address this unmet need, Vincere Biosciences has initiated a platform to develop small molecules
targeting the parkin-USP30 ubiquitination pathway, which represents a key regulator of mitochondrial
homeostasis, as a means of slowing disease progression. Converging lines of evidence – human
pharmacology, genetics, tissue pathology and animal model studies – indicate that deficits in mitochondrial
quality control pathways underlie PD pathogenes. While parkin, an E3 ubiquitin ligase, drives mitophagy by
adding ubiquitin chains to proteins on damaged mitochondria, USP30 removes these chains to inhibit
clearance of the damaged mitochondria, thus acting as the yin to parkin’s yang. Of note, functional genomic
studies in mammalian cells and flies have validated USP30 as a key target of mitochondrial quality control.
While mitochondrial abnormalities have long been implicated in sporadic PD, compelling scientific rationale
also now exists for restoring mitochondrial health in AD. By inhibiting USP30, we aim to indirectly enhance
parkin’s downstream signaling, thereby increasing mitophagy and restoring mitochondrial homeostasis. In so
doing, we will test the hypothesis that USP30 inhibitors promote the clearance of damaged
mitochondria, thereby attenuating the pathogenic cascade associated with PD pathogenesis.We have identified several hit compounds that potently inhibit USP30 activity in vitro, and demonstrate
cellular activity without cytotoxicity in human primary fibroblast cells. Moreover, our exciting preliminary data
indicate that we have rigorous flow scheme assays and starting chemical scaffolds in place to deliver: two
distinct lead series with IP potential for lead optimization (Aim 1); and, up to 12 optimized compounds for
further in vivo pharmacokinetic (PK) and target modulation/efficacy assessment and preclinical development
(Aim 2). In the proposed Phase I studies, we will answer the following technical questions: 1) Can we identify
potent and patentable USP30 inhibitors with sufficient selectivity; that, 2) Induce mitophagy in human cells
without cytotoxicity and effects of basal mitochondrial membrane potential; and, 3) Display desired in vitro
ADME properties engineered to enable in vivo proof of concept studies and preclinical development in Phase
II? A future Phase II will carry these molecules through in vivo PK, PK-Pharmacodynamic (PK-PD) research,
and preclinical development (Investigational New Drug (IND)-enabling studies) to position our molecules, for
out-license or partnership with big pharma/biotech, who have already expressed interest in our program.PROJECT NARRATIVE
The proposed Phase I research will establish the technical/scientific merit and feasibility of developing the first
disease-modifying therapy for the treatment of Parkinson’s disease (PD), an age-associated
neurodegenerative disorder second only to Alzheimer’s disease (AD) in prevalence. Simply put, Vincere
Biosciences aims to develop small molecules targeting the parkin-USP30 ubiquitination pathway, which
represents a key regulator of mitochondrial homeostasis, a process known to go awry in PD and AD. Through
the proposed studies, the team seeks to identify potent and patentable small molecules that inhibit the activity
of the enzyme USP30 as a means of promoting the clearance of damaged mitochondria, thus slowing disease
progression and improving the quality of life for millions of PD and AD patients worldwide.