PARP-2 Inhibitors

Poly(ADP-ribose) polymerase 2 (PARP-2) is a nuclear enzyme that plays a crucial role in the cellular response to DNA damage and maintenance of genomic stability. As a member of the PARP enzyme family, PARP-2 is primarily involved in the repair of single-strand DNA breaks (SSBs) through the process of base excision repair (BER). Upon detection of DNA damage, PARP-2 catalyzes the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to target proteins, including itself, forming poly(ADP-ribose) (PAR) chains. These PAR chains serve as recruitment platforms for DNA repair factors, facilitating the assembly of repair complexes at sites of DNA damage. Additionally, PARylation by PARP-2 is involved in the regulation of chromatin structure and transcriptional activity, further emphasizing its importance in maintaining genomic integrity and cellular homeostasis. Inhibition of PARP-2 activity presents a promising strategy for research of various diseases, particularly cancer. By blocking the enzymatic activity of PARP-2, inhibitors disrupt the repair of SSBs, leading to the accumulation of unrepaired DNA damage and subsequent cell death. The mechanism of PARP-2 inhibition typically involves the competitive binding of small molecules to the catalytic domain of PARP-2, thereby disrupting its interaction with NAD+ and subsequent PARylation activity. Additionally, some inhibitors may induce a conformational change in the PARP-2 enzyme, rendering it inactive or promoting its degradation. Importantly, the specificity of PARP-2 inhibitors is a critical consideration, as off-target effects may impact cellular functions and contribute to adverse effects.