# Targeting the DNA repair enzyme apurinic/apyrimidinic endonuclease (APE1) to treat cancer

> **NIH NIH R43** · XPOSE THERAPEUTICS, INC. · 2020 · $297,741

## Abstract

Cells respond to increases in DNA damage by upregulating their DNA damage response (DDR) pathways.
Replicative stress, increased cellular metabolism and exposure to chemotherapeutic agents all contribute to
elevated levels of DNA damage in cancer cells. The base excision repair (BER) pathway corrects damage to
single DNA bases through the action of several enzymes, including the central participant, apurinic/apyrimidinic
endonuclease 1 (APE1). Several studies have demonstrated an association between increased APE1 levels and
enhanced growth, migration, and drug resistance in human tumor cells, as well as with decreased patient survival
overall. To date, APE1 has been implicated in over 20 human cancers, making this enzyme an attractive target
for the development of future anticancer therapies. There are currently no inhibitors of the DNA repair activity of
APE1 in the clinic. A newly developed high-throughput crystallography-based fragment screen has resulted in
high resolution crystal structures of chemical fragments bound to the endonuclease site of APE1. These are the
first experimental 3D structures of APE1 bound to drug-like molecules, thereby resolving a primary bottleneck in
the path to inhibitor development. In this Phase I study, we propose to elaborate these fragment hits into inhibitors
of APE1 through a combination of computational and medicinal chemistry, structural biology, and biochemical
and biophysical assays. Completion of this Phase I proposal will enable a Phase II application to expand the
SAR and optimize the drug-like properties of the lead compound.

## Key facts

- **NIH application ID:** 10079779
- **Project number:** 1R43CA254552-01
- **Recipient organization:** XPOSE THERAPEUTICS, INC.
- **Principal Investigator:** Patricia Pellicena
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $297,741
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10079779

## Citation

> US National Institutes of Health, RePORTER application 10079779, Targeting the DNA repair enzyme apurinic/apyrimidinic endonuclease (APE1) to treat cancer (1R43CA254552-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10079779. Licensed CC0.

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