Company: NCNA
Filing Date: 2025-03-20
Form Type: 20-F
Source: 0000950170-25-042709
Chunk: 128

Company: NuCana plc
Filing Date: 2025-03-20
Form: 20-F
Item: Item 4
Chunk 128
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5-FU and capecitabine (Xeloda®), form a ternary complex with TS and MTHF, directly inhibiting the enzyme and preventing dTMP synthesis. This halts DNA synthesis, leading to cell death in rapidly proliferating cancer cells.
 
2. Indirect Inhibition: Antifolates, such as methotrexate (Jylamvo®), indirectly inhibit TS by depleting cellular pools of reduced folate cofactors required for TS activity. Other antifolates like pemetrexed (Alimta®) inhibit multiple folate-dependent enzymes, including TS, amplifying the disruption of nucleotide synthesis.
 

 
 NUC-3373 is a targeted TS inhibitor and is pre-activated, enabling efficient intracellular generation of the active anti-cancer metabolite known as fluorodeoxyuridine monophosphate, or FUDR-MP. This anti-cancer metabolite is also generated by drugs, such as 5-FU, capecitabine, and floxuridine, although at much lower levels. NUC-3373 is able to generate high intracellular levels of FUDR-MP and cause greater inhibition of the target enzyme TS because it enters cancer cells independently of membrane transporters, by-passes complex enzymatic conversion, and overcomes potential cancer resistance mechanisms. In addition to TS inhibition, the high levels of FUDR-MP that are generated by NUC-3373 can be misincorporated into the cancer cells DNA causing replicative stress, DNA damage and apoptosis. Furthermore, NUC-3373 causes release of damage associated molecular patterns, or DAMPs, from cancer cells, which can potentiate an anti-cancer immune response, as shown below.

 
5-FU and its Limitations
 
 First introduced in 1957, 5-FU remains a cornerstone of treatment for patients with many types of cancers, including all gastrointestinal malignancies (including colorectal, gastric, pancreatic and small bowel), breast and head and neck cancers.
 
 Four other drugs have been approved that aim to generate the same active anti-cancer metabolite as 5-FU: fluorodeoxyuridine, or Floxuridine, marketed as FUDR ®; capecitabine, marketed as Xeloda ®; UFT, marketed as Uftoral®; and S-1, marketed as Teysuno®.
 The anti-cancer activity of 5-FU and its other forms, F