Company: NCNA
Filing Date: 2025-03-20
Form Type: 20-F
Source: 0000950170-25-042709
Chunk: 121

Company: NuCana plc
Filing Date: 2025-03-20
Form: 20-F
Item: Item 4
Chunk 121
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8: A Transformation of 3’-dA
 NUC-7738 is a ProTide transformation of 3’-dA, also known as cordycepin, a nucleoside analog that was originally isolated from the fungus Cordyceps sinensis in 1950. Since that time, 3’-dA has shown potent anti-cancer activity in preclinical studies, but has not been successfully developed or approved as a treatment for patients with cancer due to rapid breakdown by the enzyme ADA. The cytotoxic effect of 3’-dA is largely attributed to the generation of the active anti-cancer metabolite, 3’-deoxyadenosine triphosphate, or 3’-dATP, which disrupts RNA polyadenylation, profoundly impacts gene expression in cancer cells, and targets multiple aspects of the TME. Similar to our other ProTides, NUC-7738 is designed to generate the active anti-cancer metabolite of 3’-dA directly inside cells, bypassing the key limitations associated with breakdown, transportation and activation.
 3’-dA and its limitations
 Similar to other nucleoside analogs, major shortcomings have limited the successful clinical development of 3’-dA.
 1. Subject to breakdown. 3’-dA is rapidly broken down by the enzyme ADA, preventing its activation and generation of its active anti-cancer form. As a result, the anti-cancer effect of 3’-dA is readily negated by ADA. This rapid breakdown is the key limiting factor that has prevented the successful development of 3’-dA in the clinic.
 2. Requires active transport. 3’-dA requires the nucleoside transporter, hENT1, to cross the cancer cell membrane. Therefore, hENT1-deficient cancer cells are highly resistant to 3’-dA.
 3. Requires activation within the cancer cell. 3’-dA must be converted to its active form once inside the cancer cell. The rate-limiting step of activation requires the addition of the first phosphate group, in this case by an enzyme called adenosine kinase, or AK. This phosphorylated form of 3’-dA, 3’-dA monophosphate, or 3’-dAMP, is subsequently converted into 3’-dA diphosphate, or 3’-dADP, which