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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
journal contribution
posted on 2014-02-27, 00:00 authored by Magdalena Slusarczyk, Monica
Huerta Lopez, Jan Balzarini, Malcolm Mason, Wen G. Jiang, Sarah Blagden, Emely Thompson, Essam Ghazaly, Christopher McGuiganGemcitabine
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.
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Clinical DevelopmentGemcitabinecancer resistance mechanismsProTide 6 fnucleoside transportersNew AgentProTide Technologyphosphoramidate motifcancer cell resistancegemcitabine phosphoramidate prodrugsSuccessful Approachtumor cell linesdeoxycytidine kinasepancreatic cancer xenograftsProTide approachtumor volumesefficacy signalsnucleoside analogueNUC6 f activationanticancer agentscytostatic activityKey Cancer Resistance Mechanisms6 fcancer therapy
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