A dihydrofolate reductase inhibitor (DHFR inhibitor) is a molecule that inhibits the function of
dihydrofolate reductase, and is a type of
antifolate.
Since folate is needed by rapidly dividing cells to make
thymine, this effect may be used to therapeutic advantage. For example,
methotrexate is used as cancer chemotherapy because it can prevent
neoplastic cells from dividing.[1][2] Bacteria also need DHFR to grow and multiply and hence inhibitors selective for bacterial vs. host DHFR have found application as antibacterial agents.[3] An extensive review of the chemical space of small-molecules that inhibit DHFR is summarized in
Classes of small-molecules employed as inhibitors of dihydrofolate reductase include diaminoquinazoline and diaminopyrroloquinazoline, Most of the above specified inhibitors are structural analogues of the substrate dihydrofolate and bind to the active site of the enzyme. Further, it has been recently shown that, in E. coli DHFR, allosteric site binders can inhibit the enzyme either uncompetitively or non-competitively. The examples provided below are specific molecules belonging to one of the above-mentioned classes.
Oral
piritrexim, a treatment for metastatic urothelial cancer.[5]
Cycloguanil, a metabolite of
proguanil (a component of the oral antimalarial atovaquone-proguanil, or
Malarone), although this has been called into question (see its article)
References
^Huennekens FM (1994). "The methotrexate story: a paradigm for development of cancer chemotherapeutic agents". Advances in Enzyme Regulation. 34: 397–419.
doi:
10.1016/0065-2571(94)90025-6.
PMID7942284.