Application of ProTide technology to gemcitabine: a successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development.

doi:10.1021/jm401853a

Paper

Application of ProTide technology to gemcitabine: a successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development.

Published Feb 14, 2014 · Magdalena Ślusarczyk, M. Lopez, J. Balzarini

Journal of medicinal chemistry

Q1 SJR score

135

Citations

5

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Abstract

Gemcitabine is a nucleoside analogue commonly used in cancer therapy but with limited efficacy due to a high susceptibility to cancer cell resistance. The addition of a phosphoramidate motif to the gemcitabine can protect it against many of the key cancer resistance mechanisms. We have synthesized a series of gemcitabine phosphoramidate prodrugs and screened for cytostatic activity in a range of different tumor cell lines. Among the synthesized compounds, one in particular (NUC-1031, 6f) was shown to be potent in vitro. Importantly, compared with gemcitabine, 6f activation was significantly less dependent on deoxycytidine kinase and on nucleoside transporters, and it was resistant to cytidine deaminase-mediated degradation. Moreover, 6f showed a significant reduction in tumor volumes in vivo in pancreatic cancer xenografts. The ProTide 6f is now in clinical development with encouraging efficacy signals in a Phase I/II study, which strongly supports the ProTide approach to generate promising new anticancer agents.

In Vitro Study

Highly Cited

Study Snapshot

ProTide technology successfully synthesized a new gemcitabine phosphoramidate prodrug (NUC-1031) that overcomes key cancer resistance mechanisms and shows promising efficacy in pancreatic cancer xenografts.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Application of ProTide technology to gemcitabine: a successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development.

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References

Pancreatic Cancer: A Review.

Molecular advances in pancreatic cancer treatment show promise for improved outcomes, but more research is needed to translate these advances into clinical trials.

Gemcitabine versus Modified Gemcitabine: a review of several promising chemical modifications.

Modified gemcitabine can improve its metabolic stability, cytotoxic activity, and resistance, potentially improving chemotherapy outcomes.

Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126

Lipophilic derivatives elacytarabine and CP-4126 show independent uptake and long retention in cancer cells, making them suitable for novel clinical applications.

Phosphoramidate ProTides of the anticancer agent FUDR successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside.

ProTides of the anticancer agent FUDR show promise as promising new derivatives that bypass active transport and kinase-mediated activation, and are resistant to metabolic deactivation by phosphorolytic enzymes.

The cytostatic activity of NUC-3073, a phosphoramidate prodrug of 5-fluoro-2'-deoxyuridine, is independent of activation by thymidine kinase and insensitive to degradation by phosphorolytic enzymes.

NUC-3073 is a novel 5-FdUrd phosphoramidate prodrug that maintains its antiproliferative activity in thymidine kinase-deficient tumor cells and is insensitive to degradation by phosphorolytic enzymes.

Citations

Chemical Space of Fluorinated Nucleosides/Nucleotides in Biomedical Research and Anticancer Drug Discovery

Fluorinated nucleosides have shown success in treating various cancers due to their improved metabolic stability, pharmacokinetic, and pharmacodynamic properties.

Therapeutic Potential Of M@B40 (M = Mg and Ca) Fullerene as a Drug Delivery System for Gemcitabine Anti‐Lung Cancer Drug: A DFT Approach

M@B40 (M = Mg and Ca) fullerene shows potential as a drug delivery system for gemcitabine, an anti-lung cancer drug, with high drug loading capacity and rapid desorption.

Microwave-Accelerated Synthesis of Novel Triphosphate Nucleoside Prodrugs: Expanding the Therapeutic Arsenal of Anticancer Agents

Microwave-accelerated synthesis of novel triphosphate nucleoside prodrugs, such as clofarabine and gemcitabine, shows potential for expanding anticancer drug arsenal and demonstrating good chemical and rat serum stability.

Thio-ProTide strategy: A novel H2S donor–drug conjugate (DDC) alleviates hepatic injury via innate lysosomal targeting

The novel H2S donor-drug conjugate (DDC) based on the thio-ProTide scaffold effectively alleviates liver injury and promotes hepatoprotection by targeting lysosomes and lipid peroxidation.

2′-Fluorinated nucleoside chemistry for new drug discovery: achievements and prospects

Fluorinated nucleosides show therapeutic promise for treating viral infections and cancer, with azvudine being approved for COVID-19 treatment and other fluorinated nucleosides in clinical trials or approved for use in patients.

Defining the mode of action of cisplatin combined with NUC-1031, a phosphoramidate modification of gemcitabine

NUC-1031 combined with cisplatin increases and occurs earlier DNA damage in biliary tract and ovarian cancer cells, potentially mitigating its effects through increased RRM1 expression.

Nucleo(s)tide metabolism as basis for drug development; the Anne Simmonds award lecture.

Drug development based on understanding purine and pyrimidine metabolism has led to treatments for various diseases, including inflammation, neurological disorders, and cancer.