Company: NCNA
Filing Date: 2025-03-20
Form Type: 20-F
Source: 0000950170-25-042709
Chunk: 127

Company: NuCana plc
Filing Date: 2025-03-20
Form: 20-F
Item: Item 4
Chunk 127
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 we expect to initiate an expansion of the NuTide:701 trial of NUC-7738 in combination with pembrolizumab in patients with metastatic melanoma and announce data from this NuTide:701 expansion study. We also anticipate obtaining regulatory guidance from the FDA on our registration strategy for NUC-7738 in melanoma in 2025.
 

NUC-3373: A Targeted Thymidylate Synthase Inhibitor
 
NUC-3373 is a targeted TS inhibitor designed to overcome the major shortcomings and pharmacologic challenges that limit the clinical utility of other TS inhibitors, such as 5-FU. We believe NUC-3373 has significant commercial potential as TS inhibitors, such as 5-FU remain some of the most important and widely used cancer therapies in the world. NUC-3373 has been designed to improve the efficacy and safety profile, as well as reduce the administration burdens, associated with 5-FU. We are advancing NUC-3373 in the clinic and developing this new chemical entity as a potential treatment for patients with solid tumors.
The Importance of Thymidylate Synthase in Cancer
  TS is an enzyme crucial for the de novo synthesis of deoxythymidine monophosphate, or dTMP, or thymidine, a nucleotide essential for DNA synthesis and repair. TS catalyzes the reductive methylation of deoxyuridine monophosphate, or dUMP, to dTMP, using 5,10-methylene tetrahydrofolate, or MTHF, as a cofactor. This reaction provides the only direct source of thymidine in cells and is therefore crucial for DNA replication and cellular proliferation.
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 In rapidly dividing cancer cells, the demand for DNA synthesis increases substantially, necessitating elevated TS activity. Consequently, TS is often upregulated in cancer cells, making it a critical target for anti-cancer agents. Inhibiting TS leads to thymidine depletion, DNA damage, disruption of DNA synthesis, and ultimately apoptosis or cell death. This approach is particularly effective in cancer cells due to their higher proliferation rates compared to normal cells.
 
 Anti-cancer agents targeting TS exploit this dependency by interfering with the enzyme's function through 2 routes:
 
1. Direct Inhibition: Fluoropyrimidines, such as