Discovery of a Novel Class of Potent Human Deoxyuridine Triphosphatase Inhibitors Remarkably Enhancing the Antitumor Activity of Thymidylate Synthase Inhibitors

Abstract

Inhibition of human deoxyuridine triphosphatase (dUTPase) has been identified as a promising approach to enhance the efficacy of 5-fluorouracil (5-FU)-based chemotherapy. This study describes the development of a novel class of dUTPase inhibitors based on the structure-activity relationship (SAR) studies of uracil derivatives. Starting from the weak inhibitor 7 (IC(50) = 100 μM), we developed compound 26, which is the most potent human dUTPase inhibitor (IC(50) = 0.021 μM) reported to date. Not only does compound 26 significantly enhance the growth inhibition activity of 5-fluoro-2'-deoxyuridine (FdUrd) against HeLa S3 cells in vitro (EC(50) = 0.075 μM) but also shows robust antitumor activity against MX-1 breast cancer xenograft model in mice when administered orally with a continuous infusion of 5-FU. This is the first in vivo evidence that human dUTPase inhibitors enhance the antitumor activity of TS inhibitors. On the basis of these findings, it was concluded that compound 26 is a promising candidate for clinical development.

Deoxyribonucleotide metabolism, mutagenesis and cancer

“…In fact, dUTP pools and dUMP residues in DNA accumulate in cells treated with fluorinated pyrimidines 129 . Consistent with this idea is the finding that inhibiting dUTPase activity potentiates the action of thymidylate synthase inhibitors 130 . Accumulation of 5-fluoro-dUTP also occurs, with its incorporation into DNA as F-dUMP 128,129 .…”

Uracil DNA glycosylase initiates degradation of HIV-1 cDNA containing misincorporated dUTP and prevents viral integration

“…5A). These findings suggest that dUTPase inhibitors might be a useful strategy to increase protection of CD4+ T cells (58,59). The therapeutic index of this approach would depend on the ability to specifically direct uracil into the replicating virus while preserving the integrity of the host genomic DNA (i.e., the relative rates of DNA replication of the viral and human polymerases and the effectiveness of nuclear uracil base excision repair in removing nascent uracils from host genomic DNA).…”

DCTPP1 attenuates the sensitivity of human gastric cancer cells to 5-fluorouracil by up-regulating MDR1 expression epigenetically

“…Certain NTP-PPases are identified in mammalians with similar biological functions, such as dUTPase [11], ITPase [12] and MTH1 [13, 14]. Moreover, dUTPase and MTH1 are reported to be associated with carcinogenesis and tumor progression [15–18], potentiating their significance in clinic [16, 19, 20]. …”