Binding of the anticancer drug ZD1694 to E. coli thymidylate synthase: assessing specificity and affinity

Structure
E E Rutenber, R M Stroud

Abstract

Thymidylate synthase (TS) catalyzes the reductive methylation of deoxyuridine monophosphate (dUMP) by 5, 10-methylenetetrahydrofolate (CH2H4folate) to form deoxythymidine monophosphate (dTMP) and dihydrofolate (H2folate). The essential role of TS in the cell life cycle makes it an attractive target for the development of substrate and cofactor-based inhibitors that may find efficacy as anticancer and antiproliferative drugs. Antifolates that compete specifically with the binding of CH2H4 folate include the cofactor analog CB3717 (10-propargyl-5,8-dideazafolate). However, the development of potent cofactor analog inhibitors of TS, such as CB3717, as drugs has been slowed by their toxicity, which often becomes apparent as hepatic and renal toxicity mediated by the specific chemistry of the compound. Attempts to abolish toxicity in human patients while preserving potency against the target enzyme, have led to the development of ZD1694, which has already shown significant activity against colorectal tumours. The three dimensional crystallographic structure of ZD1694 in complex with dUMP and Escherichia coli TS has been determined to a resolution of 2.2 . This was used to evaluate the specific structural determinants of ZD1694 pote...Continue Reading

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Citations

Mar 30, 2004·Journal of Molecular Biology·Binqing Q WeiBrian K Shoichet
Aug 9, 2002·Biochemical Pharmacology·Clasina L van der WiltGodefridus J Peters
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