Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors
Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors
复制标题
DOI：
10.1038/nbt.2121
复制
发表时间：
2012-03-01
影响因子：
46.9
通讯作者：
Weigelt, Johan
中科院分区：
文献类型：
--
作者：
Wahlberg, Elisabet;Karlberg, Tobias;Weigelt, Johan
聚ADP-核糖聚合酶（PARP）家族蛋白的抑制剂目前作为癌症治疗剂在临床试验中，然而这些化合物中的许多的特异性是未知的。在这里，我们评估了一系列185种小分子抑制剂，包括临床测试的研究试剂和化合物，以结合17种人类PARP家族成员中的13种的催化结构域，包括端锚聚合酶TNKS 1和TNKS 2。许多最知名的抑制剂，包括TIQ-A、6（5 H）-菲啶酮、奥拉帕尼、ABT-888和rucaparib，与几种PARP家族成员结合，表明这些分子缺乏特异性，具有混杂的抑制活性。我们还确定了五个TNKS 2配体复合物和四个PARP 14配体复合物的X射线晶体结构。除了显示大多数PARP抑制剂结合多个靶标外，这些结果还为新抑制剂的设计提供了见解。
Inhibitors of poly-ADP-ribose polymerase (PARP) family proteins are currently in clinical trials as cancer therapeutics, yet the specificity of many of these compounds is unknown. Here we evaluated a series of 185 small-molecule inhibitors, including research reagents and compounds being tested clinically, for the ability to bind to the catalytic domains of 13 of the 17 human PARP family members including the tankyrases, TNKS1 and TNKS2. Many of the best-known inhibitors, including TIQ-A, 6(5H)-phenanthridinone, olaparib, ABT-888 and rucaparib, bound to several PARP family members, suggesting that these molecules lack specificity and have promiscuous inhibitory activity. We also determined X-ray crystal structures for five TNKS2 ligand complexes and four PARP14 ligand complexes. In addition to showing that the majority of PARP inhibitors bind multiple targets, these results provide insight into the design of new inhibitors.