Identification and Characterization of Novel Inhibitors of Human Poly(ADP-Ribose) Polymerase-1.

Poly(ADP-ribose) polymerases (PARP) are a family of enzymes that were proven to play an essential role in the initiation and activation of DNA repair processes in the case of DNA single-strand breaks. The inhibition of PARP enzymes might be a promising option for the treatment of several challenging types of cancers, including triple-negative breast cancer (TNBC) and non-small cell lung carcinoma (NSCLC). This study utilizes several techniques to screen the compound collection of the Leibniz Institute of Plant Biochemistry (IPB) to identify novel hPARP-1 inhibitors. First, an in silico pharmacophore-based docking study was conducted to virtually screen compounds with potential inhibitory effects. To evaluate these compounds in vitro, a cell-free enzyme assay was developed, optimized, and employed to identify hPARP-1 inhibitors, resulting in the discovery of two novel scaffolds represented by compounds and , with the latter being the most active one from the compound library. Furthermore, fluorescence microscopy and synergism assays were performed to investigate the cellular and nuclear pathways of hPARP-1 inhibitor and its potential synergistic effect with the DNA-damaging agent temozolomide. The findings suggest that the compound requires further lead optimization to enhance its ability to target the nuclear PARP enzyme effectively. Nonetheless, this new scaffold demonstrated a five-fold higher PARP inhibitory activity at the enzyme level compared to the core structure of olaparib (OLP), phthalazin-1(2)-one.