Company: NCNA
Filing Date: 2025-03-20
Form Type: 20-F
Source: 0000950170-25-042709
Chunk: 122

Company: NuCana plc
Filing Date: 2025-03-20
Form: 20-F
Item: Item 4
Chunk 122
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 is then converted to 3’-dATP.
 4. Poor PK properties. 3’-dA has a short half-life both in plasma and intracellularly, due to rapid deamination by the enzyme ADA. These poor PK properties lead to dosing administration challenges and have also prevented the clinical development of 3’-dA as a cancer therapy.
 Our Solution: NUC-7738
 NUC-7738 is a ProTide transformation of 3’-dA, specifically designed to generate the active anti-cancer metabolite, 3’-dATP, in cancer cells. Importantly, NUC-7738 is not a substrate for ADA and is therefore not broken down by this enzyme. This results in greater stability and increased generation of the active anti-cancer metabolite 3’-dATP following administration. NUC-7738 is highly lipophilic and is able to enter cells independently of nucleoside transporters, including hENT1. Once inside the cancer cell, NUC-7738 is presented in the phosphorylated form, 3’-dAMP, thus bypassing the first rate-limiting phosphorylation step by AK required to generate the active anti-cancer metabolite 3’-dATP. These attributes result in significantly higher levels of the active anti-cancer metabolite 3’-dATP inside cancer cells compared to 3’-dA. Primarily, 3’-dATP disrupts RNA polyadenylation, profoundly impacts gene expression in cancer cells and targets multiple aspects of the TME, as summarized below.
<{self.tag} alt="{self.alt}" src="{self.src}">NUC-7738 Preclinical Data
 NUC-7738 is resistant to breakdown. In our preclinical studies in human leukemia cell lines, NUC-7738, unlike 3’-dA, was resistant to breakdown by the enzyme ADA, which rapidly breaks down 3’-dA into an inactive metabolite and is a major factor in reducing the potential clinical benefit of 3’-dA. The ability of NUC-7738 to resist breakdown by ADA results in greater stability and much higher intracellular concentrations of the active anti-cancer metabolite, 3’-dATP. In addition, NUC-7738 does not have the dosing administration challenges that have also limited the clinical utility of 3’-dA.
 NUC-