Thymidylate Synthase Inhibition in Colorectal Cancer Therapeutics

Thymidylate synthase inhibition remains a pillar of colorectal cancer therapy through impairment of de novo thymidine synthesis. TS, the sole enzyme catalysing conversion of deoxyuridylate to deoxythymidylate, is the key molecular target of fluoropyrimidine drugs such as 5-fluorouracil and antifolate agents. By depleting the nucleotide pool necessary for DNA replication, TS inhibitors induce replication stress, DNA damage and apoptotic cell death in rapidly dividing tumour cells. Clinical regimens combining 5-fluorouracil with leucovorin co-administration, as well as next-generation antifolates and oral prodrugs, have improved survival in both adjuvant and metastatic settings. Nonetheless, intrinsic and acquired resistance mechanisms, including TS overexpression, modifications in folate metabolism and activation of compensatory DNA repair pathways, limit the long-term efficacy of current therapies. Recent efforts seek to enhance specificity and overcome resistance through novel small-molecule inhibitors, non-classical antifolate chemotypes, tumour-responsive prodrugs and nanodelivery platforms. These strategies aim to refine the therapeutic index, attenuate off-target toxicity and reinstate drug sensitivity in refractory disease.

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Thymidylate Synthase Inhibition in Colorectal Cancer Therapeutics publication trend

The graph below shows the total number of articles in thymidylate synthase inhibition in colorectal cancer therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Thymidylate synthase (TS): Enzyme responsible for de novo conversion of deoxyuridine monophosphate to deoxythymidine monophosphate, essential for DNA synthesis in proliferating cells.

5-Fluorouracil (5-FU): Fluorinated pyrimidine analogue that inhibits TS by forming a stable ternary complex with the enzyme and its folate cofactor, leading to disruption of DNA replication.

Antifolate inhibitor: Small molecule that mimics natural folate cofactors and binds TS to prevent dTMP synthesis and induce tumour cell death.

Prodrug: Pharmacologically inert precursor converted in vivo into an active agent, often by tumour-specific enzymes, to enhance selectivity and reduce systemic toxicity.

Nanodelivery system: Nanoscale vehicle engineered to transport and release drugs in a controlled manner, improving pharmacokinetics, tumour targeting and therapeutic index.

SUMOylation: Post-translational modification in which a small ubiquitin-like modifier is covalently attached to proteins, regulating their stability, interactions and activity.

References

1. The SUMOylated RREB1 interacts with KDM1A to induce 5‐fluorouracil resistance via upregulating thymidylate synthase and activating DNA damage response pathway in colorectal cancer. MedComm (2025).
2. First-in-class multifunctional TYMS non-classical antifolate inhibitor with potent in vivo activity that prolongs survival. JCI Insight (2023).
3. Review of Prodrug and Nanodelivery Strategies to Improve the Treatment of Colorectal Cancer with Fluoropyrimidine Drugs. Pharmaceutics (2024).