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.
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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
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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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Matherly, L.H., Gangjee, A. (2011). 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. In: Jackman, A., Leamon, C. (eds) Targeted Drug Strategies for Cancer and Inflammation. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8417-3_6
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