# In vivo Evaluation of USP30 Inhibitors in Models Relevant to Parkinson's Disease

> **NIH NIH R43** · VINCERE BIOSCIENCES, INC. · 2024 · $228,711

## Abstract

ABSTRACT
Existing treatments for Parkinson’s disease (PD), which affects 10 million people worldwide, primarily augment
dopaminergic neurotransmission to provide symptomatic benefit. No current therapy can slow or stop the
progression of PD. We propose a drug discovery platform to develop small molecules targeting the parkin-USP30
mitophagy pathway, which represents a key regulator of mitochondrial homeostasis. Converging lines of
evidence from human genetics, tissue pathology and biochemical studies from sporadic PD patients, and animal
model studies indicate that deficits in Mitophagy are a modifiable contributor to PD pathogenesis. Specifically,
inhibition or knockdown of the deubiquitinating enzyme USP30 can enhance mitophagy in a variety of cell types
and infers neuroprotection in two fruit fly models (pink1 deficiency and paraquat toxicity). However, studies
examining neurodegeneration in larger animals such as rodents are an unfilled gap in knowledge that should be
addressed prior to development of USP30 inhibitors as therapeutics for PD. In the proposed Aims, we will test
the hypothesis that USP30 inhibitor small molecules will protect against neurodegeneration induced by a
mitochondrial toxin MPTP, or a-synuclein preformed fibrils – both models with links to Parkinson’s disease and
mitophagy. Our preliminary data demonstrate that we have generated a series of small molecules that potently
and selectively inhibit USP30 activity in vitro, and demonstrate cellular activity without cytotoxicity in differentiated
neuronal cell lines. Top compounds have good in vitro ADME properties and a lead and back up compound have
been identified with excellent rat and mouse plasma and brain PK profiles which place us in a unique position to
examine the proposed hypothesis. If successful, the studies proposed in this application will justify further
investment toward development of our small molecules through Investigational New Drug filing (IND)-enabling
studies, out-license, or partnership with big pharma or biotech for further clinical development.

## Key facts

- **NIH application ID:** 10931716
- **Project number:** 5R43NS127693-02
- **Recipient organization:** VINCERE BIOSCIENCES, INC.
- **Principal Investigator:** Bahareh Behrouz
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $228,711
- **Award type:** 5
- **Project period:** 2023-09-19 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931716

## Citation

> US National Institutes of Health, RePORTER application 10931716, In vivo Evaluation of USP30 Inhibitors in Models Relevant to Parkinson's Disease (5R43NS127693-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10931716. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*