# Identification of small molecule inhibitors of the DDI2 protease

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $77,925

## Abstract

PROJECT SUMMARY
Proteasome inhibitors are currently being used in the clinic against Multiple myeloma. This
approach is thought to work at least in part because cancer cells appear to rely more heavily on
proteasomes than do normal cells. However, our previous studies showed that proteasome
inhibition invokes an adaptive program driven by the transcription factor NRF1 which
upregulates proteasome genes resulting in the recovery of proteasome activity, thus limiting the
efficacy of this approach. Consistent with this notion, our recent work suggests that depletion of
NRF1 potentiates the action of proteasome inhibition therapy in a breast cancer xenograft
model. Taking advantage of the fact that a protease DDI2 is essential for NRF1 activation, the
parent grant aims to identify small molecule inhibitors of this protease that could be used to
enhance the efficacy of proteasome inhibitors. In line with the goals of the parent grant, and
based on recent preliminary data, this supplement aims to characterize the role of the protease
function of DDI2 in proteasome inhibitor-induced proteotoxic stress response mediated by
NRF1. This will facilitate the characterization of the DDI2 inhibitors that emerge from the high-
throughput screen that is being implemented in the parent grant.

## Key facts

- **NIH application ID:** 10979902
- **Project number:** 3R01CA279255-02S1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Gary L. Kleiger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $77,925
- **Award type:** 3
- **Project period:** 2023-04-10 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979902

## Citation

> US National Institutes of Health, RePORTER application 10979902, Identification of small molecule inhibitors of the DDI2 protease (3R01CA279255-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979902. Licensed CC0.

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