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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

Slusarczyk, Magdalena, Huerta Lopez, Monica, Balzarini, Jan, Mason, Malcolm David, Jiang, Wen Guo, Blagden, Sarah, Thompson, Emely, Ghazaly, Essam and McGuigan, Christopher 2014. 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 of Medicinal Chemistry 57 (4) , pp. 1531-1542. 10.1021/jm401853a

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Publisher: American Chemical Society
ISSN: 0022-2623
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 2 December 2013
Last Modified: 16 Jul 2019 21:55
URI: http://orca.cf.ac.uk/id/eprint/58756

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