PARP-7 Inhibitors

Chemical inhibitors of PARP-7 operate by various mechanisms to impede the protein's function, which is pivotal in the DNA damage repair pathway. Rucaparib, Olaparib, Veliparib, Talazoparib, Niraparib, Pamiparib, and AZD2461 act by binding to the NAD+ binding site of PARP-7. This binding mimics the structure of NAD+ and competitively inhibits the enzyme's catalytic activity, thus preventing PARP-7 from performing its role in the ADP-ribosylation of target proteins. This interference with the ADP-ribosylation process is crucial because it halts the repair of single-strand DNA breaks, an essential function of PARP-7. Talazoparib, specifically, also traps PARP-7 on DNA where damage occurs, amplifying the inhibition by not just blocking the enzymatic activity but also by stalling the enzyme in a complex with DNA, which exacerbates the inhibition of DNA repair.

Furthermore, UPF-1069, PJ34, INO-1001, 3-Aminobenzamide, and AG14361 share a common inhibitory tactic; these chemicals bind directly to the active site of PARP-7, effectively obstructing its enzymatic function. UPF-1069 and PJ34 occupy the NAD+ binding site, thus directly preventing PARP-7 from engaging in its normal ADP-ribosyltransferase activity. INO-1001 and 3-Aminobenzamide mimic the structure of nicotinamide, a part of the NAD+ molecule, which results in competitive inhibition. AG14361 excels in binding to the catalytic site of PARP-7, blocking the critical transfer of ADP-ribose units to acceptor proteins needed for DNA repair. By inhibiting this transfer, AG14361 disrupts the PARP-dependent DNA damage response, which is a testament to the chemical's potent inhibitory effect on PARP-7's function in cellular processes.