Poly(ADP-ribose) polymerase inhibition: past, present and future

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Poly(ADP-ribosyl)ation is a key post-translational modification catalyzed by poly(ADP-ribose) polymerase 1 (PARP1).
• PARP1 plays critical roles in DNA repair, gene transcription, and cell death pathways.
• Dysregulation of PARP1 is implicated in various diseases, notably cancers with DNA repair defects.

Purpose of the Study:

• To provide a comprehensive review of PARP biology and medicinal chemistry.
• To summarize the pathophysiological roles of PARP.
• To highlight current opportunities and challenges in PARP inhibitor development and application.

Main Methods:

• Literature review of PARP biology and PARP inhibitor research.
• Analysis of PARP1's involvement in cellular processes and disease pathogenesis.
• Discussion of clinical applications and future directions for PARP inhibitors.

Main Results:

• Over 50 years of research have elucidated PARP1's functions and therapeutic potential.
• Four PARP inhibitors are currently approved for cancer treatment, exploiting tumor cell sensitivity.
• PARP inhibitors demonstrate therapeutic promise beyond oncology.

Conclusions:

• PARP inhibitors represent a significant advancement in cancer therapy.
• Addressing challenges like inhibitor resistance is crucial for optimizing cancer treatment.
• Repurposing PARP inhibitors for non-oncological diseases offers new therapeutic avenues.