# Identification of CNS-Penetrant Tryptophan 2,3-Dioxygenase Degrading Ligands

> **NIH NIH R21** · PURDUE UNIVERSITY · 2022 · $235,901

## Abstract

ABSTRACT
Tryptophan 2,3-dioxygenase (TDO) is a key modulator of physiological neurogenesis and anxiety-related
behavior. Misregulated neuronal TDO activity causes elevated levels of tryptophan-kynurenine pathway
metabolites, which in turn, causes depression, brain degeneration, and neurodegenerative Alzheimer's,
Parkinson's, and Huntington's diseases. However, a critical need remains for identifying new agents that function
through innovative mechanisms to probe a range of pharmacological hypotheses regarding central TDO action,
ultimately advancing our overall pharmacological knowledge, and to also serve as leads for downstream
medicinal chemistry optimization, thus helping people live long healthy lives. To identify innovative inhibitors, we
engaged in a joint basic science-clinical study that identified a non-catalytic L-tryptophan (L-Trp) binding site in
human TDO that binds L-Trp surprisingly much tighter than the catalytic heme site. The newly discovered L-Trp
binding site is involved in regulating TDO activity and stability by suppressing ubiquitin-dependent degradation
when loaded with L-Trp. This finding has inspired us to propose a central hypothesis that this newly discovered
signaling site is an Achilles' heel of TDO for drug development. This application will fill the critical need to identify
CNS-penetrant protein-degrading ligands for exploring their biomedical potential. Towards this end, we will
employ our rigorous understanding of the underlying chemistry and biology to design compounds with a novel
mode of action that destabilize the signaling site of TDO or bind without enhancing the protein stability. These
agents will not target the catalytic activity of TDO but instead will disrupt its degradation resistance signal. We
will assess the effects of promising compounds on human TDO in cellular models to validate the innovative
approach and target. In the end, this work will open the door for designing revolutionarily new centrally-active
inhibitors targeting human TDO.

## Key facts

- **NIH application ID:** 10511398
- **Project number:** 1R21AG078775-01
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Ryan A Altman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $235,901
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10511398

## Citation

> US National Institutes of Health, RePORTER application 10511398, Identification of CNS-Penetrant Tryptophan 2,3-Dioxygenase Degrading Ligands (1R21AG078775-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10511398. Licensed CC0.

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