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Updated: Jan 30, 2026

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Discovery of Macrocyclic Inhibitors of Apurinic/Apyrimidinic Endonuclease 1

Richard Trilles1, Dmitri Beglov2, Qiujia Chen

  • 1Department of Chemistry and Center for Molecular Discovery (BU-CMD) , Boston University , Boston , Massachusetts 02215 , United States.

Journal of Medicinal Chemistry
|January 18, 2019
PubMed

Insights

Apurinic/apyrimidinic endonuclease 1 (APE1) is a cancer target. Researchers developed macrocycles that inhibit APE1 activity and show promise for cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Apurinic/apyrimidinic endonuclease 1 (APE1) is a key enzyme in DNA repair.
  • APE1 is upregulated in various cancers and contributes to therapeutic resistance.
  • APE1 is recognized as a significant target for cancer drug development.

Purpose of the Study:

  • To identify small molecule binding sites on APE1.
  • To design and synthesize novel macrocycles inhibiting APE1.
  • To evaluate the efficacy of these macrocycles in cancer cells.

Main Methods:

  • High-resolution crystal structures and FTMAP analysis to identify APE1 binding hot spots.
  • Hot-spot-guided docking and screening of a macrocycle library for APE1 inhibition.
  • Iterative design, synthesis, and testing of macrocycles for APE1 inhibition, cancer cell cytotoxicity, and DNA damage modulation.

Main Results:

  • Identified specific hot spots for small molecule binding on APE1.
  • Developed a library of drug-like macrocycles with potent APE1 endonuclease inhibitory activity.
  • Demonstrated that selected macrocycles exhibit cytotoxicity against cancer cells and modulate DNA damage, indicating target engagement.

Conclusions:

  • Macrocycles are a promising class of compounds for targeting APE1.
  • The identified hot spots provide a basis for rational drug design against APE1.
  • This approach offers a potential new therapeutic strategy for cancers involving APE1.

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