Joshua Rabinowitz: Therapy that robs cancer of its growth potential

Nov. 2, 2021

By blocking a key enzyme, researchers have developed a new approach that could treat tumors, blood cancers and autoimmune disorders.

Researchers at Princeton have found a way to slow the growth of tumors by targeting a key enzyme involved in the conversion of a common dietary amino acid, serine, into building blocks of DNA called purines. They discovered a handful of small molecules that inhibit this enzyme, known as serine hydroxymethyl transferase (SHMT).

The team reported in 2017 that SHMT-inhibitors can block the growth of many human cancers, and that B-cell lymphomas were particularly sensitive. In 2020, they showed in mice that SHMT inhibition offers a complementary strategy to the chemotherapy drug methotrexate for treatment of acute T-cell leukemia. The researchers believe that SHMT inhibitors could block malignant solid tumors, blood cancers, and autoimmune disorders including rheumatoid arthritis, psoriasis, lupus, and Crohn’s disease.

SHMT functions enzymatically to create simple molecules called one-carbon units, which are carried by co-factors known as folates, and are key inputs to purine synthesis. The inhibition of other aspects of folate metabolism is an established mechanism of therapy for a variety of human cancers and autoimmune diseases. For example, permetrexed, a leading treatment for lung cancer that is based on discoveries made at Princeton, targets folate metabolism.

Until the work by Rabinowitz and team, there were no published inhibitors of SHMT enzymes in mammals, including humans. Their work covers inhibitors of two kinds of SHMT, one located in the main body of the cell, and the other in the organelle known as the mitochondria.

"We were surprised to discover that a subset of previously identified compounds that inhibit SHMT in plants also show efficacy against the mammalian form of this enzyme. We’ve now made major progress towards turning these initial leads into drugs.”
– Joshua Rabinowitz

Multiple 3D molecule models

Small molecules that block an enzyme known as serine hydroxymethyl transferase (SHMT) may be a winning strategy against cancer and autoimmune disorders.

Innovators:
Joshua Rabinowitz, Professor of
Chemistry and the Lewis-Sigler
Institute for Integrative Genomics
Gregory Ducker, Assistant Professor,
University of Utah
Hahn Kim, Director, Princeton Small
Molecule Screening Center
Jonathan Ghergurovich, M.D./Ph.D.
Student, Robert Wood Johnson
Medical School

Collaborators:
Zemer Gitai, Edwin Grant Conklin
Professor of Biology; Daniel Herranz,
Assistant Professor of Pharmacology
at Rutgers University

Development status:
U.S. patents have been issued. The
technology and related intellectual
property have been exclusively licensed
by a subsidiary of the Barer Institute,
a cancer drug development initiative
of Rafael Holdings Inc.

Funding:
National Institutes of Health

Learn more:
Email: joshr@princeton.edu
Website: scholar.princeton.edu/rabinowitz

Licensing contact:
Laurie Viglione-Tzodikov
Associate Director
Office of Technology Licensing
Email: tzodikov@princeton.edu