# Validation of non-electrophile Nrf2 activators for WTC relevant pulmonary indications

> **NIH ALLCDC U01** · SCRIPPS FLORIDA · 2020 · $499,883

## Abstract

The current proposal is designed to lay the foundation for a medicinal-chemistry driven translational
project to optimize a non-electrophilic Nrf2 activator. Nrf2 is the body's master regulator for defense against
oxidative stress. Nrf2 is a transcription factor and is activated in oxidative environments through inhibition of
the ubiquitin ligase Keap1. In oxidative environments, oxidation of redox-active cysteines on the surface of
Keap1 leads to its inactivation. This increases Nrf2 levels and up-regulates the expression of Nrf2 target
genes, which represent an array of proteins designed to mitigate oxidative stress. Traditionally Nrf2 activators
were weak oxidants that covalently react with the intended Keap1 cysteine but also modify numerous
unintended proteins. Nrf2 activators have had narrow therapeutic windows due to toxicity resulting from their
non-specific reactivity. This proposal is unique in the use of non-electrophilic Nrf2 activators discovered in our
lab that disrupt Nrf2 ubiquitination without covalent modification through disruption of protein-protein
interactions. We have seen excellent induction of Nrf2 target genes in vivo without signs of toxicity at the
tested doses.
 Nrf2 is an attractive target for pulmonary fibrotic diseases. Disease models have demonstrated that
oxidative stress plays a key role in the development of pulmonary fibrosis and modulation of Nrf2 signaling
chemically and genetically impact disease progression. World Trade Center responders have two to five times
elevated risk of pulmonary fibrosis, which increases with intensity and duration of exposure to WTC
dust/debris and work on the debris pile. WTC responders are younger than the average pulmonary fibrosis
patient, and improved treatments that slow or stop the progression of pulmonary fibrosis and increase life
span are needed. WTC-relevant pulmonary models will be used to test the lead Nrf2 activator as a stand-
alone treatment and in concert with a recently approved drug for idiopathic pulmonary fibrosis. There is no
cure for pulmonary fibrosis, and while two new therapies have shown a benefit in slowing the decline of forced
vital capacity (the volume of air that can be forcibly exhaled after taking a deep breath), they have not
demonstrated increased lifespan. Improved therapies working independently or providing additive benefit
when given together with current medications would have a significant impact on human health.

## Key facts

- **NIH application ID:** 10064367
- **Project number:** 1U01OH012054-01
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Michael Darin Cameron
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** ALLCDC
- **Fiscal year:** 2020
- **Award amount:** $499,883
- **Award type:** 1
- **Project period:** 2020-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064367

## Citation

> US National Institutes of Health, RePORTER application 10064367, Validation of non-electrophile Nrf2 activators for WTC relevant pulmonary indications (1U01OH012054-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10064367. Licensed CC0.

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