Binding of the anticancer drug ZD1694 to E. coli thymidylate synthase: assessing specificity and affinity.
Rutenber, E.E., Stroud, R.M.(1996) Structure 4: 1317-1324
- PubMed: 8939755 
- DOI: https://doi.org/10.1016/s0969-2126(96)00139-6
- Primary Citation of Related Structures:  
2KCE - PubMed 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.
Organizational Affiliation: 
Department of Biochemistry and Biophysics, University of California at San Francisco, 94143-0448, USA. stroud@msg.ucsf.edu