Company: NCNA
Filing Date: 2025-03-20
Form Type: 20-F
Source: 0000950170-25-042709
Chunk: 123

Company: NuCana plc
Filing Date: 2025-03-20
Form: 20-F
Item: Item 4
Chunk 123
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7738 enters cancer cells independently of nucleoside transporters. In human leukemia cell lines, inhibition of nucleoside transporter activity did not have an effect on the cytotoxicity of NUC-7738 or on its ability to generate the active anti-cancer metabolite, 3’-dATP, demonstrating that the activity of NUC-7738 is not dependent on nucleoside transporters. By contrast, the activity of 3’-dA was reduced in the presence of nucleoside transporter inhibitors, as shown by a decrease in cytotoxicity as well as in the ability to generate 3’-dATP.
 NUC-7738 does not require metabolism to 3’-dAMP. As NUC-7738 is presented in the phosphorylated form, 3’-dAMP, it bypasses the first rate-limiting phosphorylation step by the enzyme AK which is required for 3’-dA to generate the active anti-cancer metabolite, 3’-dATP.
 NUC-7738 has greater anti-cancer activity than 3’-dA. In a preclinical study, we examined the in vitro cytotoxic activity of NUC-7738 across a range of different human cancer cell lines, including leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, T-cell leukemia, multiple myeloma, pancreas, colon, liver and breast cancers, as compared with 3’-dA. NUC-7738 was found, in 16 of the 20 cell lines examined in this study, to be more potent than 3’-dA when comparing the concentrations of the respective compounds required to kill 50% of the cancer cells. In three leukemia cell lines, NUC-7738 was found to be more than 50-times more potent than 3’-dA.
 NUC-7738 affects multiple cellular pathways. A series of in vitro experiments have shown that the disruption of polyadenylation by NUC-7738 affects many cellular pathways, including those associated with antigen presentation and T-cell activation, PD-L1 processing, lipid metabolism, cancer cell metabolism, and ribosomal biogenesis. These changes are induced in many different cancer cell lines where polyadenylation of RNA is frequently abnormal.
NUC-7738 Development Strategy and Ongoing Clinical Trials
 We are developing NUC-7738 for patients with either solid or hematological malignancies based on the broad activity seen