Development and therapeutic potential of DNA-dependent protein kinase inhibitors

Bioorg Chem. 2024 Sep:150:107608. doi: 10.1016/j.bioorg.2024.107608. Epub 2024 Jun 29.

Abstract

The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future.

Keywords: Cancer therapy; DDR; DNA-PK; SAR; Small molecule inhibitors.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • DNA-Activated Protein Kinase* / antagonists & inhibitors
  • DNA-Activated Protein Kinase* / metabolism
  • Drug Development
  • Humans
  • Molecular Structure
  • Neoplasms / drug therapy
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Structure-Activity Relationship

Substances

  • DNA-Activated Protein Kinase
  • Protein Kinase Inhibitors
  • Antineoplastic Agents