Avoid the trap: Targeting PARP1 beyond human malignancy

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Poly(ADP-ribose) polymerase 1 (PARP1) is crucial for DNA damage response via poly(ADP-ribosyl)ation (PARylation).
• PARP1 inhibitors are effective in homologous recombination-deficient cancers.
• Aberrant PARP1 activation in non-oncological diseases causes NAD+ depletion, PAR formation, cell death, and tissue damage.

Purpose of the Study:

• To review the biology and implications of PARP1 trapping.
• To discuss novel PARP1 PROTAC compounds as non-trapping degraders.
• To explore the potential of these compounds in non-oncological diseases.

Main Methods:

• Literature review of PARP1 biology, inhibitors, and trapping mechanisms.
• Analysis of recent developments in PARP1 PROTAC technology.
• Discussion of disease models and therapeutic potential.

Main Results:

• PARP1 trapping by current inhibitors leads to DNA damage, immune response, and cytotoxicity.
• PARP1 deletion shows protective effects in animal models.
• PARP1 PROTACs offer a "non-trapping" degradation strategy.

Conclusions:

• PARP1 trapping is a significant concern with existing PARP1 inhibitors.
• PARP1 PROTACs represent a promising therapeutic strategy for non-oncological diseases.
• Targeted degradation of PARP1 may overcome limitations of current inhibitors.