Inhibitors of inosine monophosphate dehydrogenase as potential chemotherapeutic agents

Inosine monophosphate dehydrogenase (IMPDH, E.C.1.1.1.205), an NAD-dependent enzyme that controls de novo synthesis of purine nucleotides, is an important target for the development of chemotherapeutic agents. The concentration of IMPDH is known to increase in tumour cells and activated lymphocytes. Thus, inhibition of IMPDH should result in anticancer and immunosuppressive activities. Since there is an increased demand for purine nucleotides in virus-infected cells needed for RNA and DNA synthesis, inhibition of IMPDH may also lead to antiviral activity. IMPDH enzymes from bacteria, parasites and mammalian sources differ significantly. Such differences can be exploited for the development of antibacterial or antiparasitic agents. A review, which covers the development of the field up to 1998, was published in this Journal [Pankiewicz KW, Expert Opin. Ther. Patents (1999) 9(1):55-65]. This article describes recent studies of molecular structure, mechanism of action and interactions of the enzyme with the co-factor and inhibitors. Perspectives on the development of a new generation of potent and specific inhibitors of IMPDH based on these accomplishments are discussed.