# Small molecule modulators of ΔFosB function

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $609,848

## Abstract

PROJECT SUMMARY
There is an urgent need for novel therapeutics to treat drug addiction. One potential novel drug target that
plays a key role in this devastating disorder is ΔFosB. ΔFosB accumulates in highly specific regions of the
brain (in particular the nucleus accumbens) in response to cocaine or other drugs of abuse. ΔFosB mediates
increases in drug-seeking behavior seen after prior drug exposure. As a transcription factor, ΔFosB regulates
the expression of many genes crucial to drug addiction, including the AMPA glutamate receptor subunit GluA2
and cyclin-dependent kinase 5 (Cdk5). ΔFosB can both repress and activate gene transcription, but the
molecular basis of this dual action is not known. One explanation is that ΔFosB forms both heterodimers with
JunD as well as homodimers with itself, and that these two ΔFosB-containing species differentially regulate
gene transcription. We seek to validate the therapeutic potential of ΔFosB, and to delineate its molecular
mechanisms. To this end, our goal is to leverage compounds that target ΔFosB species in vivo. We
hypothesize that, by regulating ΔFosB with small molecules, we can exploit ΔFosB to strategically regulate
key genes and overcome harmful neuronal and behavioral adaptations induced by chronic cocaine. Our
approach is to develop potent in vivo chemical probes that target ΔFosB and discriminate between ΔFosB
homodimers and heterodimers. We demonstrated with first generation scaffolds that pharmacologically
targeting ΔFosB elicited biological and behavioral responses in mice chronically treated with cocaine. We have
now identified new scaffolds with more drug-like properties, but low micromolar activity, which we have
validated in vitro. We propose to: 1) improve the potency of our probes through chemical optimization and
iterative testing, 2) demonstrate that our compounds directly bind ΔFosB and reveal their mechanism-of-action
using structural biology, and 3) measure the impact of our probes in vivo both on the behavioral responses to
cocaine, and on the transcription of GluA2 and Cdk5. The rationale for this proposal is that improved probes
will enable us to test the therapeutic potential of ΔFosB as a viable drug target to ameliorate aspects of drug
addiction. In addition, our improved probes will enable us to delineate aspects of ΔFosB in vivo (in particular
the role of ΔFosB homodimers vs. heterodimers). This proposal is innovative because it will yield chemical
tools for a novel and non-traditional putative therapeutic target for which no probes are currently available.
Importantly, we will be able to test whether ΔFosB can be used as a conduit to safely regulate specific genes
that maintain the addicted state by harnessing the highly region-specific accumulation of ΔFosB in the nucleus
accumbens in response to drugs of abuse. Furthermore, our probes will enable us to reveal completely new
mechanistic information on ΔFosB which cannot be easily gained using current techniques. Thi...

## Key facts

- **NIH application ID:** 9948610
- **Project number:** 5R01DA040621-05
- **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:** 2020
- **Award amount:** $609,848
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948610

## Citation

> US National Institutes of Health, RePORTER application 9948610, Small molecule modulators of ΔFosB function (5R01DA040621-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9948610. Licensed CC0.

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