(Dr Magdalena Slusarczyk; Dr Michaela Serpi; Dr Fabrizio Pertusati)

In collaboration with NuCana, a clinical-stage biopharmaceutical company, we continue to utilize our scientifically driven approach (ProTides technology) to design anticancer agents with aim to overcome the key resistance mechanisms associated with nucleoside analogues. These mechanisms include: limited uptake by cancer cells; poor conversion of the drug into the active 5′-di- and 5’-triphosphate forms, and rapid degradation into toxic by-products. We believe that a transformation of both well-established-clinically and novel anti-tumour nucleoside analogues into phosphate prodrugs can significantly enhance their effectiveness in the cancer therapies.

Currently, two ProTide agents (NUC-1031 and NUC-3373) that have been developed in Prof. Chris McGuigan’s laboratory are undergoing clinical trials in patients with advanced solid tumours. In addition, one ProTide (NUC-7738) is under preclinical development and entry to first-in-human Phase I study is planned for 2018.

NUC-1031 is the gemcitabine L-alanine-based 5’-phosphoramidate designed to overcome all three of the resistance mechanisms (cellular uptake, kinase mediated phosphorylation and deamination) that have been associated with a poor survival prognosis to gemcitabine therapy. The first-in-human Phase I study in patients with advanced solid tumours was opened in 2012 and encouraging pharmacokinetics and a favourable efficacy and safety profile have been reported for NUC-1031 in this study. The plasma half-life of NUC-1031 was more favourable than gemcitabine (7.3 hours versus 1.5 hours), and NUC-1031 achieved 217 x higher intracellular dFd-CTP levels than those reported for gemcitabine. Final results of the first-in-human Phase I study of NUC-1031 in patients with solid tumours indicated the achievement of durable disease control in a high proportion of patients including patients refractory to, or who relapsed on prior gemcitabine therapy. Currently, NUC-1031 is being assessed in several clinical studies for the treatment of patients with ovarian, biliary and pancreatic cancers.

NUC-3373 is the FUDR L-alanine-based 5’-ProTide which shown in preclinical in vitro study to exert its cytostatic activity independently on thymidine kinase in TK-deficient cell lines. In addition, NUC-3373 was resistant to the degradative action of catabolic enzymes such as thymidine phosphorylase (TP), an enzyme often upregulated in tumour cells or expressed in mycoplasma-infected tumour tissue, and dihydropyrimidine dehydrogenase (DPD), an enzyme abundantly expressed in the liver. The cytostatic potency of ProTide was maintained in the tumour cell lines that lack hENT1 transporter (CEM/hEnt-0) whilst that of FUDR was reduced by 63-fold. Moreover, NUC-3373 generated in vitro up to 363-fold higher intracellular levels of FdUMP in comparison with 5-FU in human colorectal cancer cell line HT29. In vivo NUC-3373 achieved significantly greater tumour volume reduction than 5-FU in the human colorectal cancer HT29 mouse xenograft model. In 2016, NUC-3373 entered into a Phase I clinical study in patients with advanced solid tumours.

NUC-7738 is the ProTide of cordycepin, a nucleoside analogue with anti-cancer properties reported in preclinical studies. NUC-7738 was designed to bypass the resistance mechanisms connected to nucleoside analogues namely: transportation, activation and breakdown and deliver an active metabolite directly into the cell. The preliminary in vitro testing in a panel of cancer cell lines revealed up to 50-fold greater anti-cancer activity for NUC-7738 in comparison with the parent nucleoside in certain cell lines. Currently, a preclinical toxicology studies are undergoing and Phase I study in patients with solid tumours in planned.