Research progress in DNA damage response (DDR)-targeting modulators: From hits to clinical candidates

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Synthetic lethality is a validated cancer treatment approach.
• Its application has expanded beyond BRCA-deficient tumors.
• DNA Damage Response (DDR) targets are increasingly important.

Purpose of the Study:

• To review DDR-associated synthetic lethality targets.
• To discuss targeted modulators (inhibitors, degraders).
• To explore rational design, benefits, and limitations of DDR-targeted drugs.

Main Methods:

• Literature review of synthetic lethality and DDR targets.
• Analysis of emerging targeted modulators.
• Discussion of drug development strategies.

Main Results:

• Identified key DDR targets: WRN, USP1, PARP, ATR, DNA-PK, PRMT5, POLQ, WEE1.
• Highlighted development of inhibitors and degraders for these targets.
• Emphasized rational design principles and clinical trial advancements.

Conclusions:

• DDR-targeted synthetic lethality presents a significant advancement in cancer therapy.
• Targeted modulators offer precise therapeutic strategies.
• The field shows a promising future for novel drug development.