Discovery of Novel Antifolate Inhibitors of De Novo Purine Nucleotide Biosynthesis with Selectivity for High Affinity Folate Receptors and the Proton-Coupled Folate Transporter Over the Reduced Folate Carrier for Cellular Entry

Chapter

Abstract

Lack of drug selectivity is one of the major causes of the failure of cancer chemotherapy. This Chapter describes studies that explore the concept of therapeutic targeting solid tumors using folate-receptor (FR) and proton-coupled folate transporter (PCFT)-targeted antifolates that exhibit limited transport by the ubiquitously expressed reduced folate carrier (RFC). We describe our recent studies with novel 6-substituted pyrrolo- and thieno[2,3-d]pyrimidine antifolates as selective substrates of FR and PCFT over RFC, which are potent inhibitors of de novo purine nucleotide biosynthesis at β-glycinamide ribonucleotide formyltransferase. Our results document potent in vitro and in vivo antitumor activities for the lead compounds of these series.

Keywords

Antifolate Folate receptor Proton-coupled folate transporter Reduced folate carrier Glycinamide ribonucleotide formyl transferase 

Abbreviations

AICARFTase

5-Amino-4-imidazolecarboxamide ribonucleotide formyltransferase

CHO

Chinese hamster ovary

FGAR

Formyl glycinamide ribonucleotide

FR

Folate receptor

GAR

Glycinamide ribonucleotide

GARFTase

Glycinamide ribonucleotide formyltransferase

IC50

Fifty percent inhibition

LCV

Leucovorin

LMTX

Lometrexol

MTX

Methotrexate

PCFT

Proton-coupled folate transporter

PMX

Pemetrexed

RFC

Reduced folate carrier

RTX

Raltitrexed

SCID

Severe combined immunodeficient

Notes

Acknowledgments

This work was supported in part by grants from the National Institutes of Health, National Cancer Institute, CA53535 (LHM), CA125153 (AG), and CA152316 (LHM and AG), a grant from the Mesothelioma Applied Research Foundation (LHM), and a pilot grant from the Barbara Ann Karmanos Cancer Institute (LHM). We acknowledge the contributions of present and past members of the Matherly and Gangjee laboratories who contributed to the studies described in this chapter. Special thanks go to Dr. Lisa Polin of the Karmanos Cancer Institute who performed the in vivo mouse experiments with compound 14.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Developmental TherapeuticsBarbara Ann Karmanos Cancer InstituteDetroitUSA
  2. 2.Department of OncologyWayne State University School of MedicineDetroitUSA
  3. 3.Department of PharmacologyWayne State University School of MedicineDetroitUSA

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