For decades the standard of care for cancer treatment, especially colon cancer, has been 5-fluorouracil (5-FU).  5-FU, the fluorinated derivative of the RNA base uracil, induces cell death by acting as an irreversible inhibitor of thymidylate synthase (TS), a key enzyme in DNA synthesis and cell division. Cancer cells are able to survive TS inhibition by over expressing dUTPase, a non-redundant enzyme responsible for the conversion of the deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP).  By over-expressing dUTPase, resistant cells are able to reduce the dUTP levels and prevent concentration-dependent uracil incorporation into DNA. Herein, we report the structure-based design and synthesis of novel dUTPase inhibitors that act as a new class of anticancer agents that are suitable for cancers resistant to 5-FU and other TS inhibitors.

Design and synthesis of novel anticancer agents targeting uracil-DNA repair

243rd National Meeting (2012)

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