Novel opportunities for thymidylate metabolism as a therapeutic target
Peter M Wilson, William Fazzone, Melissa J LaBonte, Jinxia Deng, Nouri Neamati, Robert D Ladner, Peter M Wilson, William Fazzone, Melissa J LaBonte, Jinxia Deng, Nouri Neamati, Robert D Ladner
Abstract
For over 40 years, the fluoropyrimidine 5-fluorouracil (5-FU) has remained the central agent in therapeutic regimens employed in the treatment of colorectal cancer and is frequently combined with the DNA-damaging agents oxaliplatin and irinotecan, increasing response rates and improving overall survival. However, many patients will derive little or no benefit from treatment, highlighting the need to identify novel therapeutic targets to improve the efficacy of current 5-FU-based chemotherapeutic strategies. dUTP nucleotidohydrolase (dUTPase) catalyzes the hydrolysis of dUTP to dUMP and PPi, providing substrate for thymidylate synthase (TS) and DNA synthesis and repair. Although dUTP is a normal intermediate in DNA synthesis, its accumulation and misincorporation into DNA as uracil is lethal. Importantly, uracil misincorporation represents an important mechanism of cytotoxicity induced by the TS-targeted class of chemotherapeutic agents including 5-FU. A growing body of evidence suggests that dUTPase is an important mediator of response to TS-targeted agents. In this article, we present further evidence showing that elevated expression of dUTPase can protect breast cancer cells from the expansion of the intracellular uracil pool, translating to reduced growth inhibition following treatment with 5-FU. We therefore report the implementation of in silico drug development techniques to identify and develop small-molecule inhibitors of dUTPase. As 5-FU and the oral 5-FU prodrug capecitabine remain central agents in the treatment of a variety of malignancies, the clinical utility of a small-molecule inhibitor to dUTPase represents a viable strategy to improve the clinical efficacy of these mainstay chemotherapeutic agents.
Figures
![Figure 1. Mechanism of 5-FU-induced DNA Damage](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2597111/bin/nihms-68743-f0001.jpg)
![Figure 2. Variation in dUTPase Expression in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2597111/bin/nihms-68743-f0002.jpg)
![Figure 3. Elevated dUTPase Protects Breast Cancer…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2597111/bin/nihms-68743-f0003.jpg)
Figure 4. Immunohistochemical Analysis of dUTPase in…
Figure 4. Immunohistochemical Analysis of dUTPase in Human Breast Adenocarcinoma
Formalin-fixed, paraffin-embedded breast cancer tumor…
Figure 5. Shape-merged pharmacophore model derived from…
Figure 5. Shape-merged pharmacophore model derived from Dud778
A, Dud778 mapping onto the feature model.…
Figure 6. Docking validation of Dud778-dUTPase co-crystal…
Figure 6. Docking validation of Dud778-dUTPase co-crystal structure
A, Dud778 as observed in the x-ray…
![Figure 4. Immunohistochemical Analysis of dUTPase in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2597111/bin/nihms-68743-f0004.jpg)
![Figure 5. Shape-merged pharmacophore model derived from…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2597111/bin/nihms-68743-f0005.jpg)
![Figure 6. Docking validation of Dud778-dUTPase co-crystal…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2597111/bin/nihms-68743-f0006.jpg)
Source: PubMed