Fig. 1

NUC-3373 and 5-fluorouracil mechanisms of action. NUC-3373 is a pre-activated and protected form of FUDR. It carries a phosphoramidate group which protects the FUDR-MP moiety, making it resistant to breakdown by DPD and allowing it to enter cancer cells without the need for nucleobase transporters. As NUC-3373 contains the active metabolite, FUDR-MP, it does not require phosphorylation by TK. These properties would confer NUC-3373 with more stability than 5-FU, resulting in a longer half-life and the generation of higher intracellular levels of FUDR-MP, making it a more potent inhibitor of TS than 5-FU. Abbreviations: 5-FU = 5-fluorouracil; DPD = dihydropyrimidine dehydrogenase; DHFU = dihydrofluorouracil; dTMP: deoxythymidine monophosphate; dUMP: fluorodeoxyuridine-monophosphate; FBAL = alpha-fluoro-beta-alanine; FUDR = fluorodeoxyuridine; FUDR-MP = fluorodeoxyuridine monophosphate; FUDR-DP = fluorodeoxyuridine diphosphate; FUDR-TP = fluorodeoxyuridine triphosphate; FUMP = fluorouridine monophosphate; FUDP = fluorouridine diphosphate; FUTP = fluorouridine triphosphate; FUR = fluorouridine; OPRT = orotate phosphoribosyl transferase; RR = ribonucleotide reductase; TK = thymidine kinase; TP = thymidine phosphorylase; UK = uridine kinase; UP = uridine phosphorylase