2. Academic Validation
  3. A 5'-(R)-CH3-substituted 5-fluoro-2'-deoxyuridine monophosphate reduces off-target toxicities while maintaining efficacy in a colorectal cancer model

A 5'-(R)-CH3-substituted 5-fluoro-2'-deoxyuridine monophosphate reduces off-target toxicities while maintaining efficacy in a colorectal cancer model

  • J Pharmacol Exp Ther. 2025 Nov 10;393(1):103773. doi: 10.1016/j.jpet.2025.103773.
Christopher M Monaco 1,  Nicole Pribut 1,  Chitalu C Musonda 1,  Carrie Q Sun 2,  John A Petros 2,  Ken H Liu 3,  Eric J Miller 4,  Dennis C Liotta 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Emory University College of Arts and Sciences, Atlanta, Georgia.
  • 2 Department of Urology, Emory University School of Medicine, Atlanta, Georgia.
  • 3 Department of Chemistry, Emory University College of Arts and Sciences, Atlanta, Georgia. Electronic address: [email protected].
  • 4 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia. Electronic address: [email protected].
  • 5 Department of Chemistry, Emory University College of Arts and Sciences, Atlanta, Georgia; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia. Electronic address: [email protected].
PMID: 41352320 DOI: 10.1016/j.jpet.2025.103773
Abstract

Since its approval in the early 1960s, 5-fluorouracil (5-FU) has remained an important therapeutic for the treatment of late-stage and metastatic colorectal Cancer (CRC). It acts through intracellular conversion to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) to inhibit Thymidylate Synthase (TYMS), leading to nucleotide pool imbalance, DNA damage, and disruption of tumor cell proliferation. However, 5-FU is limited by rapid clearance and off-target toxicities, which affects a large proportion of patients with CRC. To address these issues, we developed 5'-(R)-CH3-FdUMP (Me-FdUMP), a 5'-(R)-CH3-substituted analog of FdUMP that retains inhibitory activity against purified TYMS. Here, we show that Me-FdUMP is resistant to metabolism by phosphatases and kinases, reduces 5-FU formation, and enhances TYMS inhibition in a human CRC cell line. In mice, Me-FdUMP treatment led to markedly lower 5-FU exposure in the heart and bone marrow, 2 key sites of clinical toxicity. Furthermore, in a mouse xenograft model of human CRC, Me-FdUMP maintained antitumor efficacy comparable to FdUMP. Taken together, these results suggest 5'-(R)-CH3-substituted FdUMP could be a promising new approach for improving the safety of fluoropyrimidine-based therapeutics. SIGNIFICANCE STATEMENT: Current fluoropyrimidine-based therapeutics for colorectal Cancer suffer from metabolic liabilities that can often lead to severe and dose-limiting side-effects. Results reported here highlight a new fluoropyrimidine derivative with enhanced on-target activity in vitro, maintenance of antitumor efficacy in vivo, and impaired metabolism that can reduce exposure of toxic metabolites. This work represents a new strategy to address the shortcomings of current fluoropyrimidine-based therapeutics with the potential to improve patient outcomes.

Keywords

5-Fluoro-2′-deoxyuridine monophosphate; 5-Fluorouracil; Colorectal cancer; Fluoropyrimidine; Nucleoside analog; Thymidylate synthase.

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