软膜
奥拉帕尼
聚ADP核糖聚合酶
PARP抑制剂
PARP1
拓扑异构酶
化学
癌症研究
DNA修复
药理学
酶
生物
生物化学
聚合酶
DNA
作者
Junko Murai,Yves Pommier
出处
期刊:Cancer drug discovery and develogment
日期:2015-01-01
卷期号:: 261-274
被引量:9
标识
DOI:10.1007/978-3-319-14151-0_10
摘要
All PARP inhibitors in clinical development (veliparib, olaparib, niraparib, rucaparib, talazoparib) are potent submicromolar competitive NAD+ inhibitors for PARP1 and PARP2, thereby blocking PARylation reactions [i.e. formation of poly(ADPribose) polymers]. In addition, PARP trapping, which determines the anticancer activity of PARP inhibitors as single agents, is drug-specific, and PARP inhibitors can be ranked according to their PARP trapping potency: Talazoparib >> niraparib ˜ olaparib ˜ rucaparib > veliparib. The highly synergistic effects of PARP inhibitors in combination with alkylating agent (temozolomide or methyl methanesulfonate, MMS) and topoisomerase I (Top1) inhibitors (camptothecins and indenoisoquinolines) are well documented. Both classes of drugs induce DNA single-strand breaks sensed by PARP. Yet, the molecular mechanisms of synergy are different. For alkylating agents (temozolomide and MMS), both PARP trapping and PARylation inhibition account for the synergy, whereas for Top1 inhibitors, there is no involvement of PARP trapping and it is PARylation inhibition that deters the coupling of PARP with the repair enzyme, tyrosyl-DNA phosphodiesterase TDP1. In this chapter, we will review the differences between PARP inhibitors and the rationale for choosing among different PARP inhibitors in combination with alkylating agents or Top1 inhibitors.
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