# Ornithine Aminotransferase Inactivation, a New Approach for Treatment of Cancers

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $412,090

## Abstract

Project Summary/Abstract
 Recently, it was found that the enzyme ornithine aminotransferase (OAT) is overexpressed in
hepatocellular carcinoma (HCC), the most common primary malignancy of the liver and the 2nd leading cause
of cancer-related death in men (6th in women) worldwide. There are relatively few molecules known to inhibit
the activity of OAT, and those that have been reported focus on their ability to increase the concentration of
ornithine as a potential treatment for acute ammonia intoxications and hepatogenic encephalopathy. The
objective of this proposal is to use computer modeling, based on the known crystal structures of human OAT
and other PLP-dependent enzymes with our previously-active inactivators bound, to assist in the design of new
inactivators of OAT that are selective against other related enzymes to lower the potential of side effects from
off-target inhibition. Modifications to our earlier compounds will be made to improve on potency and
pharmacokinetic properties. The mechanisms of those compounds that selectively inactivate OAT will be
investigated. X-ray crystal structures of the inactivators bound to OAT will be obtained by our collaborator, Dr.
Dali Liu, to assist in further structural modifications. Compounds that are potent and selective inactivators of
OAT will be tested by Dr. Wenan Qiang against several cancer cell lines also found to overexpress OAT and
carry out PDX studies with the most effective compounds. He also will corroborate that the compounds inhibit
secretion of alpha-fetoprotein, a biomarker for HCC, and that OAT is the target. The goal is to identify one or
more compounds that are selective inhibitors/inactivators of OAT that suppress the growth of HCC, and other
cancers that overexpress OAT, in animals. These compounds would be first-in-class treatments for HCC, a
cancer that is highly resistant to both standard cancer chemotherapy and radiation therapy, and the prognosis
for recovery is very poor, as well as other OAT-expressing cancers.

## Key facts

- **NIH application ID:** 10185371
- **Project number:** 1R01CA260250-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** RICHARD B SILVERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,090
- **Award type:** 1
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10185371

## Citation

> US National Institutes of Health, RePORTER application 10185371, Ornithine Aminotransferase Inactivation, a New Approach for Treatment of Cancers (1R01CA260250-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10185371. Licensed CC0.

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