PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3
PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3
复制标题
DOI：
10.1021/cb4002014
复制
发表时间：
2013-08-01
影响因子：
4
通讯作者：
Schueler, Herwig
中科院分区：
文献类型：
--
作者：
Lindgren, Anders E. G.;Karlberg, Tobias;Schueler, Herwig
用parp抑制剂抑制adp -核糖基转移酶被认为是治疗许多癌症和缺血的一种很有前途的策略，但大多数细胞靶点的特征都很差。在这里，我们描述了一种adp -核糖基转移酶-3/聚（adp -核糖）聚合酶-3 （ARTD3）的抑制剂，一种DNA修复和有丝分裂进程的调节剂。对12个酶家族成员的体外分析表明，ARTD3具有选择性，晶体结构说明了抑制剂选择性的分子基础。该化合物在细胞中有活性，在亚微摩尔浓度下引起artd3特异性作用。我们的研究结果表明，通过靶向烟酰胺结合位点，可以对经验证的临床靶点adp -核糖转移酶-1/聚（adp -核糖）聚合酶-1的近亲进行选择性抑制。
Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12, members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.