Application of ProTide Technology to Gemcitabine:A Successful Approach to Overcome the Key Cancer Resistance MechanismsLeads to a New Agent (NUC-1031) in Clinical Development.

Gemcitabineis a nucleoside analogue commonly used in cancer therapybut with limited efficacy due to a high susceptibility to cancer cellresistance. The addition of a phosphoramidate motif to the gemcitabinecan protect it against many of the key cancer resistance mechanisms.We have synthesized a series of gemcitabine phosphoramidate prodrugsand screened for cytostatic activity in a range of different tumorcell lines. Among the synthesized compounds, one in particular (NUC-1031, 6f) was shown to be potent in vitro. Importantly,compared with gemcitabine, 6factivation was significantlyless dependent on deoxycytidine kinase and on nucleoside transporters,and it was resistant to cytidine deaminase-mediated degradation. Moreover, 6fshowed a significant reduction in tumor volumes in vivoin pancreatic cancer xenografts. The ProTide 6fis now in clinical development with encouraging efficacysignals in a Phase I/II study, which strongly supports the ProTideapproach to generate promising new anticancer agents. [ABSTRACT FROM AUTHOR]