Multi-therapies Based on PARP Inhibition: Potential Therapeutic Approaches for Cancer Treatment

Abstract

The nuclear enzymes called poly(ADP-ribose)polymerases (PARPs) are known to catalyze the process of PARylation, which plays a vital role in various cellular functions. They have become important targets for the discovery of novel antitumor drugs since their inhibition can induce significant lethality in tumor cells. Therefore, researchers all over the world have been focusing on developing novel and potent PARP inhibitors for cancer therapy. Studies have shown that PARP inhibitors and other antitumor agents, such as EZH2 and EGFR inhibitors, play a synergistic role in cancer cells. The combined inhibition of PARP and the targets with synergistic effects may provide a rational strategy to improve the effectiveness of current anticancer regimens. In this Perspective, we sum up the recent advance of PARP-targeted agents, including single-target inhibitors/degraders and dual-target inhibitors/degraders, discuss the fundamental theory of developing these dual-target agents, and give insight into the corresponding structure–activity relationships of these agents.

Indole-containing pharmaceuticals: targets, pharmacological activities, and SAR studies

“…Although other DNA repair procedures, such as error-prone nonhomologous end joining (NHEJ) or alternative end-joining pathways, can be started, which may result in mutations or chromosomal changes, 88 apoptosis and cell death in cancer cells can be brought on by further DNA damage. 89 According to the SAR graph of rucaparib (45), it can bind PARP with high affinity because of its significant H-bonds with Ser904 and Gly863 (Fig. 32b).…”

Apoptosis induction of kadsuric acid from Vietnamese Kadsura coccinea (Lem.) A. C. Smith in human pancreatic cancer cells: in vitro and in silico approach

“…However, normal cells with functional DNA repair mechanisms can tolerate PARP1 inhibition (Li et al, 2020). Several PARP1 inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, have been approved for the treatment of various types of cancer, particularly ovarian and breast cancer, and have shown promising results in clinical trials (Li et al, 2020;Tao & Wu, 2021;Zhang et al, 2022).…”

Advances in Development of Selective Antitumor Inhibitors That Target PARP-1

“…Therefore, improving the selectivity of PARP-1 inhibitors not only achieves antitumor effects but also helps in reducing the toxic effects associated with PARP-2 inhibition. As a result, improvement in selectivity and the development of selective inhibitors with high activity has become the focus and main direction for the development of a new generation of PARP inhibitors …”

“…As a result, improvement in selectivity and the development of selective inhibitors with high activity has become the focus and main direction for the development of a new generation of PARP inhibitors. 12…”