# Small molecule modulators of ΔFosB

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2022 · $625,300

## Abstract

PROJECT SUMMARY
There is an urgent need to develop effective strategies to combat drug addiction, a major public health burden.
Unfortunately, current efforts are hampered by a focus on a very limited range of drug targets. Decades of work
have established that the transcription factor DFosB plays a critical role in drug addictive behaviors in rodent
models, with validation in humans available as well. In response to chronic cocaine or opioids (e.g., heroin)
administration, DFosB mediates aspects of drug seeking, reward, self-administration, and relapse. Due to its
unusual stability, DFosB accumulates to very high levels in the brain in regions critical for reward, making it an
attractive target for addiction therapies. However, critical mechanistic aspects of DFosB function are not known,
making it difficult to pursue DFosB as a therapeutic target. It is not known how DFosB molecules are arranged
in vivo, what molecular features control their ability to bind to DNA and turn genes on or off, and whether these
features can be targeted strategically with small molecules in order to regulate DFosB function in vivo to combat
drug use disorders. We hypothesize that, by modulating ∆FosB with small molecules, we can selectively
regulate key strategic DFosB gene targets, and thereby the long-term neural and behavioral adaptations that
DFosB triggers in response to chronic drug use. To test our hypotheses, we propose to 1) optimize a series of
validated lead compounds into high-affinity chemical probes targeting DFosB in vitro and in vivo; 2) unravel how
key molecular features in DFosB regulate its actions; and 3) determine how targeting these features either with
our chemical probes or novel genetic tools alters behaviors in animal models of addiction. To this end, we have
an outstanding translational research team overseeing a robust and effective experimental platform that draws
on our prior combined work. We have already achieved important milestones. First, we have discovered that
DFosB partners not only with JunD but also with itself in order to bind DNA, and these two species are structurally
and functionally very different. Second, we have uncovered a molecular switch in ∆FosB that controls its binding
to DNA and that works differently in heteromeric vs. homomeric ∆FosB complexes. Third, we have developed a
large panel of lead compounds that target DFosB and that we can leverage to gain both fundamental mechanistic
insight into DFosB function, as well as assess their in vivo effects on addictive behaviors. Together, our work
creates a powerful, previously unavailable, and highly actionable platform to test the utility of DFosB as a
therapeutic target. The positive impact of this work will be to further de-risk DFosB as a therapeutic target by
creating comprehensive, mechanism-based knowledge onto which a drug discovery program will be anchored,
focused on a completely novel target to combat addiction. This innovative proposal will provide novel in...

## Key facts

- **NIH application ID:** 10372152
- **Project number:** 5R01DA040621-07
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** ERIC J. NESTLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $625,300
- **Award type:** 5
- **Project period:** 2016-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372152

## Citation

> US National Institutes of Health, RePORTER application 10372152, Small molecule modulators of ΔFosB (5R01DA040621-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10372152. Licensed CC0.

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