# ANTIFOLATES INHIBITORY TO FOLYLPOLYGLUTAMATE SYNTHETASE

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 1988 · $174,668

## Abstract

Mammalian folypoly-gamma-glutamate synthetase (FPGS) converts
folylmonoglutamates, the transport form of folates, into their
polyglutamate congeners by the successive addition of glutamic acid
monomers using, ATP a source of energy.  The underlying thesis of
this work is that inhibitors of FPGS will be a unique new class of
antimetabolites that will be useful as cancer chemotherapeutic
drugs.  The folylpolyglutamates are retained in cells, in contrast
to the effluxable monoglutamates, and are the preferred form of
cofactor for the folate-dependent enzymes.  FPGS has been shown to
be an essential function for a dividing cell population.  The goal
of this proposal is to design and synthesize potent and selective
inhibitors of mammalian FPGS and to study the cellular and
biochemical effects of this unique new class of folate
antimetabolites.  The synthesis of some folate analogs predicted
to be analogs of the transition states and of the intermediate
product of the FPGS reaction will be undertaken and the interaction
of these compounds with purified FPGS will be studied.  Second
generation analogs of the potent FPGS inhibitor 4-amino-4-
deoxypteroyl-L-ornithine will be prepared that penetrate the cell
membrane efficiently or that are prodrugs converted to inhibitors
in the cell.  Other compounds to be made would be more potent
analogs of this lead compound or would have no activity as
dihydrofolate reductase.  Finally, the interaction of the side
chain of folate analogs with the active site of FPGS would be
further investigated.  The effects of these new compounds will be
studied on purified mammalian FPGS and on the function of FPGS in
whole cells.

Inhibition of folate metabolism by existing antagonists of folate
metabolism (which, until recently, have been uniformly
dihydrofolate reductase inhibitors) has been very useful for
treatment of human neoplasms.  Antifolates are active against a
spectrum of malignancies arising in different tissues, have
managable toxicities, have low or non-existent mutagenic and
carcinogenic threat and are reversible by reduced folates.  We
propose that inhibitors of FPGS will share these beneficial
characteristics, yet will have a mechanism distinct from that of
classical antifolates such as methotrexate.

## Key facts

- **NIH application ID:** 3178998
- **Project number:** 2R01CA039687-04
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **SAM.gov UEI:** DVL1CMRMWRN9
- **Principal Investigator:** RICHARD G MORAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $174,668
- **Award type:** 2
- **Project period:** 1985-09-30 → 1989-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3178998

## Citation

> US National Institutes of Health, RePORTER application 3178998, ANTIFOLATES INHIBITORY TO FOLYLPOLYGLUTAMATE SYNTHETASE (2R01CA039687-04). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3178998. Licensed CC0.

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