Discovery of Highly Potent Human Deoxyuridine Triphosphatase Inhibitors Based on the Conformation Restriction Strategy

Miyahara, Seiji; Miyakoshi, Hitoshi; Yokogawa, Tatsushi; Chong, Khoon Tee; Taguchi, Junko; Muto, Toshiharu; Endoh, Kanji; Yano, Wakako; Wakasa, Takeshi; Ueno, Hiroyuki; Takao, Yayoi; Fujioka, Akio; Hashimoto, Akihiro; Itou, Kenjirou; Yamamura, Keisuke; Nomura, Makoto; Nagasawa, Hideko; Shuto, Satoshi; Fukuoka, Masayoshi

doi:10.1021/jm300416h

Cited by 20 publications

(14 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The amide linker of inhibitor 1 and sulfonamide linker of compound 2 are facing the solvent, while the terminal cyclopentyl moiety of compound 2 partially occupies the same region as the second terminal phenyl group of compound 1 . The benzylic α-methyl group of inhibitor 2 occupied the same region as the proline ring of compound 1 , providing a hypothesis for the observed stereochemical preference displayed by structurally closely related representatives of these two chemical series [29, 30]. …”

Section: Resultsmentioning

confidence: 99%

dUTPase inhibition augments replication defects of 5-Fluorouracil

et al. 2017

View full text Add to dashboard Cite

The antimetabolite 5-Fluorouracil (5-FU) is used in the treatment of various forms of cancer and has a complex mode of action. Despite 6 decades in clinical application the contribution of 5-FdUTP and dUTP [(5-F)dUTP] and 5-FUTP misincorporation into DNA and RNA respectively, for 5-FU-induced toxicity is still under debate.This study investigates DNA replication defects induced by 5-FU treatment and how (5-F)dUTP accumulation contributes to this effect. We reveal that 5-FU treatment leads to extensive problems in DNA replication fork progression, causing accumulation of cells in S-phase, DNA damage and ultimately cell death. Interestingly, these effects can be reinforced by either depletion or inhibition of the deoxyuridine triphosphatase (dUTPase, also known as DUT), highlighting the importance of (5-F)dUTP accumulation for cytotoxicity.With this study, we not only extend the current understanding of the mechanism of action of 5-FU, but also contribute to the characterization of dUTPase inhibitors. We demonstrate that pharmacological inhibition of dUTPase is a promising approach that may improve the efficacy of 5-FU treatment in the clinic.

show abstract

Section: Resultsmentioning

confidence: 99%

dUTPase inhibition augments replication defects of 5-Fluorouracil

et al. 2017

View full text Add to dashboard Cite

show abstract

“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Weil

Ghosh²,

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

119

View full text Add to dashboard Cite

Significance Misincorporation of dUTP into DNA is detrimental to eukaryotes, prokaryotes, and viruses. This study reveals the fate of uracilated HIV-1 DNA in human cells. Early stages of the viral life cycle are unaffected, but integration of uracilated viral DNA into the host genome is prevented. This effect is wholly dependent on the presence of UNG2, a nuclear enzyme that excises uracil from DNA. This study establishes that UNG2 is a restriction factor for uracilated HIV-1 DNA and explains why this pathway is not fully engaged in CD4+ T cells and macrophages.

show abstract

“…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]. …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

Gastric cancer (GC) is among the most malignant cancers with high incidence and poor prognoses worldwide as well as in China. dCTP pyrophosphatase 1 (DCTPP1) is overexpressed in GC with a poor prognosis. Given chemotherapeutic drugs share similar structures with pyrimidine nucleotides, the role of DCTPP1 in affecting the drug sensitivity in GC remains unclear and is worthy of investigation. In the present study, we reported that DCTPP1-knockdown GC cell line BGC-823 exhibited more sensitivity to 5-fluorouracil (5-FU), demonstrated by the retardation of cell proliferation, the increase in cell apoptosis, cell cycle arrest at S phase and more DNA damages. Multidrug resistance 1 (MDR1) expression was unexpectedly down-regulated in DCTPP1-knockdown BGC-823 cells together with more intracellular 5-FU accumulation. This was in large achieved by the elevated methylation in promoter region of MDR1 gene. The intracellular 5-methyl-dCTP level increased in DCTPP1-knockdown BGC-823 cells as well. More significantly, the strong correlation of DCTPP1 and MDR1 expression was detectable in clinical GC samples. Our results thus imply a novel mechanism of chemoresistance mediated by the overexpression of DCTPP1 in GC. It is achieved partially through decreasing the concentration of intracellular 5-methyl-dCTP, which in turn results in promoter hypomethylation and hyper-expression of drug resistant gene MDR1. Our study suggests DCTPP1 as a potential indicative biomarker for the predication of chemoresistance in GC.

show abstract

Discovery of Highly Potent Human Deoxyuridine Triphosphatase Inhibitors Based on the Conformation Restriction Strategy

Cited by 20 publications

References 34 publications

dUTPase inhibition augments replication defects of 5-Fluorouracil

dUTPase inhibition augments replication defects of 5-Fluorouracil

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

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

Contact Info

Product

Resources

About