Design, development, and therapeutic applications of PARP-1 selective inhibitors

Abstract

Poly(ADP-ribose) polymerase (PARP) plays a key role in DNA damage repair and has become a critical target for tumor therapy. In recent years, several PARP inhibitors, such as Olaparib and Niraparib, have achieved clinical success in breast cancer susceptibility genes (BRCA) mutant tumors by exploiting the synthetic lethality of homologous recombination-deficient cancers. However, problems have emerged in clinical application, such as hematologic toxicity, which may be related to the lack of subtype selectivity of PARP-1/-2. Selective inhibitors of PARP-1 that can overcome toxicity have emerged as a new strategy for PARP inhibitor development. In this review, we first reveal the conformational heterogeneity of the PARP-1/-2 active region through homology comparison and systematically explain the spatial topological characteristics of its selective binding pockets. Then, the structure-activity relationships of 14 reported selective inhibitors of PARP-1 are analyzed to reveal the key pharmacophores occupying the active region, as well as to characterize the specific groups bound to the selective binding domain. Finally, we discuss the structural requirements of selective PARP-1 inhibitors and propose the "secondary site contact" design strategy for the development of new PARP inhibitors.

Keywords: Tumor therapy; hematologic toxicity; homology comparison; selective PARP-1 inhibitors; structure-activity relationships.