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Dihydrofolate reductase as a therapeutic target
B I Schweitzer1, A P Dicker, J R Bertino
1Laboratory of Molecular Pharmacology, Cornell University Graduate School of Medical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Summary
Folate antagonists, like methotrexate, inhibit dihydrofolate reductase (DHFR) for cancer and inflammation treatment. New DHFR inhibitors are being developed, exploiting enzyme differences for targeted therapies.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Biochemistry
Background:
- Folate antagonists are crucial therapeutic agents used as antiinfective, antineoplastic, and antiinflammatory drugs.
- Clinically useful folate antagonists function by inhibiting dihydrofolate reductase (DHFR), an enzyme vital for DNA synthesis.
Purpose of the Study:
- To elucidate the biochemical basis for the selectivity of DHFR inhibitors like methotrexate.
- To understand the mechanisms of resistance to antifolate drugs.
- To inform the development of a new generation of DHFR inhibitors.
Main Methods:
- Investigating the structural and functional differences between microbial and mammalian DHFR active sites.
- Analyzing the biochemical mechanisms underlying drug resistance.
- Clinical trials of novel DHFR inhibitors.
Main Results:
- Species-selective inhibition of DHFR by antifolates like trimethoprim and pyrimethamine is achieved by exploiting differences in enzyme active sites.
- Significant advancements in understanding methotrexate's selectivity and resistance mechanisms have been made.
- A new generation of DHFR inhibitors is currently undergoing clinical evaluation.
Conclusions:
- Folate antagonists targeting DHFR offer diverse therapeutic applications, including anti-infective, anti-cancer, and anti-inflammatory uses.
- Understanding enzyme selectivity and resistance mechanisms is key to developing improved antifolate therapies.
- Novel DHFR inhibitors show promise for clinical application.