期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：11
DOI：10.1073/pnas.2121979119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
PARP is an important target in the treatment of cancers, particularly in patients with breast, ovarian, or prostate cancer that have compromised homologous recombination repair (i.e., BRCA
−/−). This review about inhibitors of PARP (PARPi) is for readers interested in the development of next-generation drugs for the treatment of cancer, providing insights into structure–activity relationships, in vitro vs. in vivo potency, PARP trapping, and synthetic lethality.
Selective inhibitors of PARP1 and PARP2 (PARP1/2) are used to treat cancer patients with deficiencies in the repair of DNA via homologous recombination. Here we provide a perspective on the reported potencies of the most studied of these inhibitors (olaparib, talazoparib, niraparib, rucaparib, and veliparib) in vitro and in vivo and how these numbers relate to the known structures of these inhibitors bound to the active sites of PARP1 and PARP2. We suggest that the phenomenon of PARP trapping is primarily due to the inhibition of the catalytic activity of PARP1 and that the basis for the higher potency of talazoparib compared to the other inhibitors lies in its more extensive network of interactions with conserved residues in the active site. We also consider the potential role of the recently characterized protein “Histone PARylation Factor 1” (HPF1), which interacts with PARP1/2 to form a shared active site, for the design of the next generation of inhibitors of PARP1/2.
关键词：encancer drugsinhibitor of ParpHPF1synthetic lethalitydrug specificity
