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Inhibitors of Bacterial DNA Synthesis

Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These antibiotics are selectively...
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Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
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One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
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Updated: Jun 18, 2026

Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
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A SMUG1 Inhibitor Modulates the Excision of Pyrimidine DNA Damage.

Pavitra S Thacker1, Yixuan Gao1, Lisa McPherson2

  • 1Department of Chemistry, Stanford University, Stanford, California 94305, United States.

ACS Medicinal Chemistry Letters
|June 17, 2026
PubMed
Summary

Scientists developed the first SMUG1 enzyme inhibitor, SU0617, to study DNA repair and cancer drug resistance. This new tool helps investigate how cells respond to antitumor therapies involving pyrimidine damage.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • DNA repair enzymes, particularly those surveilling pyrimidine damage, are implicated in resistance to antitumor therapies.
  • The DNA base excision repair (BER) enzyme SMUG1 is crucial for removing damaged pyrimidines, including those from cytotoxic drugs like 5-fluorodeoxyuridine (5-FdU).

Purpose of the Study:

  • To discover and develop novel inhibitors of the SMUG1 enzyme.
  • To create a chemical tool for studying DNA repair pathways and responses to nucleoside-based antitumor drugs.

Main Methods:

  • Screening of small molecules for inhibitory activity against the SMUG1 DNA repair enzyme.
  • Structure-based optimization of initial hit compounds to enhance specificity and potency.
  • Biochemical assays to determine enzyme inhibition (IC50) and assess off-target activities.

Main Results:

  • Identified sphingosine kinase inhibitor scaffolds as potential SMUG1 inhibitors.
  • Developed compound SU0617, a potent and selective SMUG1 inhibitor with an IC50 of 1.5 ± 0.1 μM.
  • Confirmed that SU0617 lacks significant kinase inhibitory activity.

Conclusions:

  • SU0617 represents the first described inhibitor scaffold for SMUG1.
  • This inhibitor provides a valuable tool for investigating SMUG1's role in DNA repair and drug resistance.
  • Further studies can utilize SU0617 to explore base excision repair pathways and cellular responses to therapeutic nucleosides.