Selective Small Molecule Inhibition of Poly(ADP-Ribose) Glycohydrolase (PARG)
Selective Small Molecule Inhibition of Poly(ADP-Ribose) Glycohydrolase (PARG)
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DOI：
10.1021/cb200506t
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发表时间：
2012-03-01
影响因子：
4
通讯作者：
Hergenrother, Paul J.
中科院分区：
文献类型：
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作者：
Finch, Kristin E.;Knezevic, Claire E.;Hergenrother, Paul J.
多聚腺苷二磷酸核糖（PAR）的翻译后修饰对于多种细胞功能是必不可少的，包括转录调节、对DNA损伤的反应和有丝分裂。细胞PAR主要由聚（ADP-核糖）聚合酶-1（PARP-1）合成。PARP-1是DNA损伤反应途径中的关键节点，并且已经描述了多种有效的PARP-1抑制剂，其中一些在临床上显示出相当大的前景用于治疗某些癌症。细胞PAR被聚（ADP-核糖）糖水解酶（PARG）有效降解，PARG是一种没有有效的、容易获得的特异性抑制剂的酶。在此，我们报告了在体外和细胞裂解物中有效抑制PARG的小分子的发现。这些有效的PARG抑制剂可以在两个化学步骤中从商业起始材料产生，并且相对于其他已知的PAR糖水解酶（ADP-核糖基水解酶3，ARH 3）和PARP-1对PARG具有完全特异性，因此将是用于研究PAR信号传导的生物化学的有用工具。
The poly(ADP-ribose) (PAR) post-translational modification is essential for diverse cellular functions, including regulation of transcription, response to DNA damage, and mitosis. Cellular PAR is predominantly synthesized by the enzyme poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a critical node in the DNA damage response pathway, and multiple potent PARP-1 inhibitors have been described, some of which show considerable promise in the clinic for the treatment of certain cancers. Cellular PAR is efficiently degraded by poly(ADP-ribose) glycohydrolase (PARG), an enzyme for which no potent, readily accessible, and specific inhibitors exist. Herein we report the discovery of small molecules that effectively inhibit PARG in vitro and in cellular lysates. These potent PARG inhibitors can be produced in two chemical steps from commercial starting materials and have complete specificity for PARG over the other known PAR glycohydrolase (ADP-ribosylhydrolase 3, ARH3) and over PARP-1 and thus will be useful tools for studying the biochemistry of PAR signaling.