# MECHANISM-BASED ENZYME INHIBITORS: NOVEL ANTIFOLATES

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 1988 · $149,665

## Abstract

The proposed project is part of a long range research effort aimed
at the development of new approaches to the chemotherapy of
proliferative diseases.  The main objective of this research is to
apply mechanistic considerations to the design and subsquent
study of novel antifolates.  The study focuses on the role of the
poly-gamma-glutamyl chain of folates and antifolates in their
cofactor activity and/or cytotoxicity, as a basis for drug design.
As specific targets, enzymes of two metabolic cycles, one
responsible for the formation and breakdown of polygultamates
and the other for the folate polyglutatmate dependent
biosynthesis of thymidylate have been chosen.

The chemical part of the project involves the rational design,
synthesis and characterization of new antifolates.  The use of
computerized molecular modelling techniques is planned to gain
insight into the active sites of target enzymes and their
interaction with drug candidates utilizing past and future
structure-activity correlations and x-ray crystallographic
structural information.  The chemical studies are coordinated with
the biochemical studies involving the metabolism and enzymology
of folyl and antifolyl polyglutamates as well as the evaluation of
the enzyme inhibitory activities of the newly synthesized
compounds.  These studies employ intact and reversibly
permeabilized L1210 murine leukemia cells and isolated enzyme
systems.  The permeabilized cell system premits the direct study
of the cellular metabolism of polyglutamates of folates and folate
analogues and their interaction with enzymes of intact metabolic
pathways.  The cytotocicity of the compounds is determined in
vitro by measuring the extent of growth inhibition of L1210
leukemia cells in suspension cultures.  It is an important goal of
the project to correlate cellular and cell-free enzyme inhibitory
activity with in vitro cytotoxicity data and to use these
correlations to predict in vivo biological activity.  The results of
this study will help to formulate future research plans including
the possibility of therapeutic applications.

In addition to their potential therapeutic utility, the proposed
analogues may serve as useful tools in the study of the essential
role of polyglutamylation in cancer cells.  The study of drug-
enzyme interactions may further our knowledge of the catalytic
mechansms of folate dependent enzymes and furnish new
rationales for inhibitor design.  Since folate metabolism is
intimately linked to nucleic acid biosynthesis and Cellular
proliferation, this research may lead to important observations in
tumor biology.

## Key facts

- **NIH application ID:** 3172824
- **Project number:** 2R01CA035212-04A2
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **SAM.gov UEI:** LMCJKRFW5R81
- **Principal Investigator:** THOMAS I KALMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $149,665
- **Award type:** 2
- **Project period:** 1983-09-30 → 1992-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172824

## Citation

> US National Institutes of Health, RePORTER application 3172824, MECHANISM-BASED ENZYME INHIBITORS: NOVEL ANTIFOLATES (2R01CA035212-04A2). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172824. Licensed CC0.

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