Enhancement of thymidylate synthase inhibition.

Molecular modeling techniques and a knowledge of thymidylate synthase protein structure have assisted in the development of several potent new inhibitors of thymidylate synthase, the enzyme mediating de novo formation of thymidylate for use in DNA synthesis. Information on several new and specific thymidylate synthase inhibitors, including ICI-D1694, 1843U89, AG-331, and AG-337, is presented. The effects of thymidylate synthase inhibition on the induction of thymidylate synthase protein synthesis have raised the question of whether thymidylate synthase inhibition alone will be sufficient to provide a desirable clinical effect. Formation of a thymidylate synthase-inhibitor complex prevents posttranscriptional regulation of thymidylate synthase synthesis, allowing for increased thymidylate synthase synthesis and the possibility of drug resistance. Therefore, recent efforts have also focused on characterizing this increase in thymidylate synthase protein induced by inhibitors of thymidylate synthase and on devising combination drug strategies that may prevent the induction of thymidylate synthase protein synthesis in addition to inhibiting thymidylate synthase activity.