A large number of cancer patients do not respond to 5-fluorouracil (5-FU) and other thymidylate synthase (TS) inhibitors, which have long being used as the standard of care for various cancers. This type of resistance can be attributed to the over-expression of the enzyme dUTPase, which allows the cells to regulate mis-incorporation of uracil through the conversion of deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP). The development of selective dUTPase inhibitors, therefore, is of great interest to cancer therapy. Through the use of in silico modeling and virtual high-throughput screening, a new class of dUTPase inhibitors was designed, synthesized, and later optimized by SAR. Subsequent phenotypic screening revealed that these optimized molecules exhibit potent anticancer effects and enhance the cytotoxicity of TS inhibitors in various cancer cell lines. These new heterocyclic small molecules represent a potentially new class of therapeutics for the treatment of resistant cancers.

Design, synthesis, and screening of novel dUTPase inhibitors for the treatment of resistant cancers

247th National Meeting (2014)

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