# Development of N-acyl fluspirilene mediated proteasome enhancement for the treatment of neurodegenerative diseases

> **NIH NIH R36** · UNIVERSITY OF VIRGINIA · 2024 · $52,081

## Abstract

Abstract. Currently there are limited therapeutic treatments to slow, prevent, or cure
neurodegenerative diseases such as Alzheimer’s Disease or Alzheimer’s-related Dementias.
Instead, most therapies rely on managing symptoms. These neurodegenerative diseases are
characterized by accumulation of intrinsically disordered proteins (IDPs) and impairment of
proteasome-mediated protein degradation. This R36 proposal aims to investigate small
molecule 20S proteasome activation as a novel strategy to resolve both pathogenic events. Our
group has identified fluspirilene and N-acyl-fluspirilene as a novel class of small molecules that
not only activate the 20S proteasome to degrade IDPs, but also overcome IDP-induced
proteasome impairment. The overarching aims of this project are to (1) identify the mechanism
by which the N-acyl-fluspirilene class selectively enhances 20S proteasome activity, and (2)
develop enhanced small molecule activators of the 20S proteasome. Successful completion of
this work will enable the rapid design, development, and identification of 20S proteasome
activators, and elucidate the role of 20S proteasome modulation in neurodegenerative diseases
as a novel therapeutic strategy for disease treatment.

## Key facts

- **NIH application ID:** 11178909
- **Project number:** 7R36AG088233-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Daniel Jose Colombani-Garay
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $52,081
- **Award type:** 7
- **Project period:** 2024-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11178909

## Citation

> US National Institutes of Health, RePORTER application 11178909, Development of N-acyl fluspirilene mediated proteasome enhancement for the treatment of neurodegenerative diseases (7R36AG088233-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11178909. Licensed CC0.

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