Among the most widely used anticancer therapeutics are agents that target DNA synthesis and repair, such as 5-fluorouracil (5-FU), that causes cell death through irreversible inhibition of thymidylate synthase (TS). In many patients with resistant cancers, however, 5-FU and other TS inhibitors become ineffective as a result of the over-expression of dUTPase, an enzyme responsible for the conversion of the deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP). Herein, we report new types of potential anticancer agents based on the inhibition of dUTPase. The structure-based design, synthesis, optimization, and growth inhibition data are presented. Through the use of phenotypic assays with our inhibitors alone and in combination with TS inhibitors, we demonstrate the potential therapeutic benefits of this approach.

Structure-based design of novel inhibitors of dUTPase as potential anticancer agents

245th National Meeting (2013)

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