Targeting ATR in Cancer therapy: A drug discovery perspective

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The ataxia telangiectasia and Rad3-related (ATR) kinase is a key regulator of the DNA damage response (DDR).
• ATR activation supports cancer cell survival under DNA damage, making it a significant therapeutic target.
• Tumors with high replication stress or DDR deficiencies are particularly vulnerable to ATR inhibition.

Purpose of the Study:

• To provide a comprehensive review of ATR's biological functions in DNA repair, cell cycle control, and cancer cell survival.
• To examine current clinical-stage ATR inhibitors (ATRi) and preclinical compounds.
• To explore novel therapeutic strategies, including next-generation ATRi, degraders, dual inhibitors, and combination therapies.

Main Methods:

• Literature review of ATR's role in DDR and cancer.
• Analysis of structure-activity relationships for preclinical ATR inhibitors.
• Evaluation of combination strategies involving ATR inhibitors and other anti-tumor agents.

Main Results:

• ATR is central to maintaining genomic stability and enabling cancer cell survival.
• Several ATR inhibitors are in clinical development, with ongoing efforts to improve their efficacy and specificity.
• Dual ATR inhibitors and combination therapies show promise for enhanced anti-tumor activity.

Conclusions:

• ATR remains a critical target for cancer therapy, especially in DDR-deficient tumors.
• Development of next-generation ATR inhibitors and rational combination strategies are essential for clinical success.
• Targeting ATR offers a promising avenue for novel cancer treatments.