# Targeting Tryptophan Dioxygenase Degradation for Suppression of Tumor Immune Evasion

> **NIH NIH R21** · PURDUE UNIVERSITY · 2022 · $220,632

## Abstract

ABSTRACT
The tryptophan degradation pathway is used to prevent unrestrained immune activation in healthy cells.
However, tumors hijack this mechanism to escape immune surveillance. The key enzymes of this pathway,
tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), are established immune checkpoint
proteins. Tumors enhance their expression to block T cell proliferation and induce T cell death, thereby avoiding
immune system surveillance and increasing tumor cell migration capacity. Thus, inhibiting these checkpoint
enzymes in cancer cells by small molecule-based therapies has emerged as a potential immunotherapeutic
strategy. There is a critical need for new agents developed from an innovative approach with a solid
understanding of their underlying chemistry and biology, to advance the overall scientific knowledge and to
ultimately help the public live long healthy lives. From a joint basic science-clinical study we identified a non-
catalytic L-tryptophan (L-Trp) binding site in human TDO, which 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 protein-degrading ligands for exploring their biomedical
potential. Towards this end, we will 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 inhibitors targeting the immune checkpoint protein human TDO.

## Key facts

- **NIH application ID:** 10436036
- **Project number:** 1R21CA270879-01
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Ryan A Altman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $220,632
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436036

## Citation

> US National Institutes of Health, RePORTER application 10436036, Targeting Tryptophan Dioxygenase Degradation for Suppression of Tumor Immune Evasion (1R21CA270879-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10436036. Licensed CC0.

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