# Investigating the Proline Cycle as a Potential Cancer Therapy Target

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2024 · $419,478

## Abstract

PROJECT SUMMARY
Proline dehydrogenase (PRODH) and Δ1-pyrroline-5-carboxylate (P5C) reductase
(PYCR) form a metabolic relationship known as the “proline cycle”, a novel pathway that
impacts cellular growth and death pathways. The proline cycle is central to the
metabolic shift that enables tumorigenesis and supports the metastatic cascade of
cancer cells. PRODH is upregulated in metastasizing breast cancer cells, and PYCR1 is
one of the most consistently upregulated enzymes across multiple cancer cell types.
Thus, proline cycle enzymes have been proposed as potential cancer drug targets. A
major goal of this project is to gain insight into whether these enzymes have binding
sites that can be exploited for small molecule binding and establish target tractability,
i.e., the likelihood of identifying modulators that interact effectively with these targets.
Initial results are encouraging, as the chemical probes developed in the first phase of
this project show activity in cellular and animal models of cancer. These results motivate
our proposal to (1) develop new and more potent reversible inhibitors of PRODH and
PYCR1, (2) explore the mechanism-based covalent inactivation of PRODH, and (3)
define the mechanistic roles of the proline cycle using chemical probes in cancer cells.
With these studies we will mechanistically dissect the role of proline metabolism in
cancer progression. We expect this knowledge will in the long-term aid the development
of new therapeutic strategies against cancer.

## Key facts

- **NIH application ID:** 10981164
- **Project number:** 2R01GM132640-03
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Donald F Becker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $419,478
- **Award type:** 2
- **Project period:** 2020-09-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981164

## Citation

> US National Institutes of Health, RePORTER application 10981164, Investigating the Proline Cycle as a Potential Cancer Therapy Target (2R01GM132640-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10981164. Licensed CC0.

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