Fig. 1

NUC-1031 and gemcitabine mechanism of action. There are three key cancer resistance mechanisms associated with a poor survival prognosis with gemcitabine therapy: transport, activation and breakdown. The transport of gemcitabine, an inactive prodrug, into cancer cells is mediated via hENT1. Once inside the cell, gemcitabine requires phosphorylation to dFdCMP by dCK, which represents the rate-limiting step for further phosphorylation to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) metabolites. Gemcitabine is also rapidly catabolised by CDA generating a metabolite. NUC-1031 was designed to overcome the key cancer resistance mechanisms associated with gemcitabine. NUC-1031 enters the cell independent of the hENT1 transporter and does not require activation by dCK. Similar to the phosphorylated forms of gemcitabine, NUC-1031 is not subject to breakdown by CDA. NUC-1031 is designed to generate and maintain higher concentrations of the anti-cancer metabolite (dFdCTP) inside the tumour compared to gemcitabine