# Design and Development of Inhibitors of Methionine Adenosyltransferase for Cancer Treatment

> **NIH NIH F32** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $50,458

## Abstract

Project Abstract
S-adenosyl-L-methionine (AdoMet) is a common methyl donor in cellular epigenetic modification
of macromolecules to regulate gene expression. Methionine adenosyltransferase (MAT) is the
sole enzyme responsible for AdoMet synthesis from ATP and methionine substrates. Three MAT
isozymes are found in humans, with only the MAT2A isoform being expressed in most tissues
and cancer cells. Over expression of MAT2A in cancer cells has been noted for some time. Recent
studies have shown that a common gene deletion in cancer cells of 5’-methylthioadenosine
phosphorylase (MTAP) creates susceptibility to MAT2A inhibition due to increased cellular
dependence on AdoMet synthesis. Our lab has previously targeted MTAP using tight-binding
transition state analogues that were successful in reducing cancer cell growth in cell culture and
mouse xenografts. Cancer cells conditioned to MTAP inhibitor resistance were analyzed and a
single gene amplification event at the MAT2A gene locus was identified. In this proposal, we will
use two powerful methods of enzyme inhibitor design, click chemistry and transition state
analogues, to target MAT2A. These innovative chemistry approaches have been applied to other
enzyme targets to generate some of the tightest binding inhibitors known. Click chemistry and
transition state analogue approaches allow for creation of bisubstrate analogues that target both
the ATP and methionine binding sites of MAT2A. This simultaneous targeting of two enzyme
active site groups increases the inhibitor affinity, as it resembles the short-lived but high-affinity
intermediate reaction species. Inhibitors generated through these methods will be subject to
structural, thermodynamic, and kinetic analysis. Efficacy of these high affinity MAT2A inhibitors
on reducing cancer cell growth and viability will be analyzed on MTAP-/- and MTAP+/+ cancer cell
lines. Co-treatment of cancer cell lines with MTAP transition state analogues will explore
synergistic effects of MTAP and MAT2A. We hypothesize that MAT2A inhibitors generated from
this work will amplify the anti-cancer effects MTAP inhibitors and provide a novel treatment for
MTAP-/- cancers.

## Key facts

- **NIH application ID:** 9899959
- **Project number:** 5F32CA225149-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Courtney Nicole Niland
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,458
- **Award type:** 5
- **Project period:** 2018-05-01 → 2021-01-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899959

## Citation

> US National Institutes of Health, RePORTER application 9899959, Design and Development of Inhibitors of Methionine Adenosyltransferase for Cancer Treatment (5F32CA225149-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9899959. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*