Abstract：
Allosteric coupling between the DNA binding site to the NAD+-binding pocket drives PARP-1 activation. This allosteric communication occurs in the reverse direction such that NAD+ mimetics can enhance PARP-1\'s affinity for DNA, referred to as type I inhibition. The cellular effects of type I inhibition are unknown, largely because of the lack of potent, membrane-permeable type I inhibitors. Here we identify the phthalazinone inhibitor AZ0108 as a type I inhibitor. Unlike the structurally related inhibitor olaparib, AZ0108 induces replication stress in tumorigenic cells. Synthesis of analogs of AZ0108 revealed features of AZ0108 that are required for type I inhibition. One analog, Pip6, showed similar type I inhibition of PARP-1 but was ∼90-fold more cytotoxic than AZ0108. Washout experiments suggest that the enhanced cytotoxicity of Pip6 compared with AZ0108 is due to prolonged target residence time on PARP-1. Pip6 represents a new class of PARP-1 inhibitors that may have unique anticancer properties.
摘要：
DNA结合位点与NAD+结合袋之间的变构偶联驱动PARP-1活化。这种变构通讯发生在相反的方向，使得NAD+模拟物可以增强PARP-1对DNA的亲和力，称为I型抑制。I型抑制的细胞作用是未知的，很大程度上是因为缺乏强大的力量，膜渗透性I型抑制剂。在这里,我们将苯并二嗪酮抑制剂AZ0108鉴定为I型抑制剂。与结构相关的抑制剂奥拉帕尼不同，AZ0108在致瘤细胞中诱导复制应激。AZ0108类似物的合成揭示了AZ0108的I型抑制所需的特征。一个模拟，Pip6对PARP-1的I型抑制作用相似，但细胞毒性比AZ0108高90倍。冲洗实验表明,与AZ0108相比,Pip6的细胞毒性增强是由于在PARP-1上的靶停留时间延长。Pip6代表一类新的PARP-1抑制剂，可能具有独特的抗癌特性。
