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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
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ATR inhibitors: from targeting the DNA damage response to exploiting synthetic lethality-A paradigm shift in Cancer

Xin Zhou1, Qi Qin1, Huizhi Yao1

  • 1Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China.

Bioorganic Chemistry
|January 30, 2026
PubMed

Insights

This review details Ataxia Telangiectasia and Rad3-related (ATR) kinase inhibitors, exploring their medicinal chemistry, clinical progress, and challenges. It outlines the path toward next-generation ATR-targeted precision medicine for cancer treatment.

Area of Science:

  • Biochemistry and Molecular Biology
  • Cancer Therapeutics
  • Medicinal Chemistry

Background:

  • Ataxia Telangiectasia and Rad3-related (ATR) kinase is crucial for the DNA replication stress response.
  • ATR kinase is a key target for synthetic lethality in DNA Damage Response (DDR)-deficient cancers.

Purpose of the Study:

  • To systematically review the molecular biology of ATR kinase.
  • To analyze the medicinal chemistry evolution of ATR inhibitors.
  • To examine clinical progress, challenges, and future directions for ATR-targeted therapies.

Main Methods:

  • Systematic review of molecular biology and medicinal chemistry literature.
  • Analysis of structure-activity relationships (SAR) for clinical ATR inhibitors (berzosertib, ceralasertib, elimusertib).
  • Evaluation of Proteolysis-Targeting Chimeras (PROTACs) and combination regimens.

Main Results:

  • Detailed SAR analysis highlights chemical modifications improving ATR inhibitor selectivity and druggability.
  • Identified limitations of PROTACs and challenges in combination therapies.
  • Analysis of dose-limiting toxicities and acquired resistance mechanisms.

Conclusions:

  • ATR inhibitors show promise but face challenges like toxicity and resistance.
  • Development of predictive biomarkers is essential for effective ATR-targeted precision medicine.
  • Future research focuses on optimizing ATR inhibitors and combination strategies for enhanced cancer treatment.
Keywords:
ATRATR inhibitorsCombination therapyReplication stressSARSynthetic lethality

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