Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib.
Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib.
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DOI：
10.1158/1535-7163.mct-13-0803
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发表时间：
2014-02
影响因子：
5.7
通讯作者：
Pommier Y
中科院分区：
文献类型：
--
作者：
Murai J;Huang SY;Renaud A;Zhang Y;Ji J;Takeda S;Morris J;Teicher B;Doroshow JH;Pommier Y
抗多聚(ADP-核糖)聚合酶(PARP)药物最初被开发作为催化抑制剂来阻断DNA单链断裂的修复。我们最近报道了几种PARP抑制剂通过捕获PARP-DNA复合体具有额外的细胞毒性机制，并且奥拉帕利布和niraparib在药理浓度下都是PARP毒物。因此，我们建议对PARP抑制剂的评价应同时基于催化PARP抑制和PARP-DNA捕获。在这里，我们评估了新型PARP抑制剂BMN 673，并比较了它与另外两种临床PARP抑制剂olaparib和rucaparib在转基因鸡DT40和人类癌细胞系中对PARP1和PARP2的影响。虽然BMN 673、olaparib和rucaparib在抑制PARP催化活性方面相似，但BMN 673捕获PARP-DNA复合体的能力是olaparib的100倍，作为单药的细胞毒性更强，而olaparib和rucaparib捕获PARP-DNA复合体的能力相似。PARP1/2基因敲除细胞对BMN 673的高抗性表明BMN 673对PARP1/2具有选择性。此外，我们还表明BMN 673通过立体特异性结合PARP1起作用，因为它的对映体LT674的效率要低几个数量级。BMN 673的细胞毒性也是奥拉帕利布和鲁卡帕里布与DNA烷化剂甲基甲烷磺酸盐(MMS)和替莫唑胺联合使用的~100倍。我们的研究表明，BMN 673是迄今为止测试的最有效的临床PARP抑制剂，在捕获PARP-DNA复合体方面具有最高的效率。
Anti-poly(ADP-ribose)polymerase (PARP) drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. We recently reported that several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP-DNA complexes, and that both olaparib and niraparib act as PARP poisons at pharmacological concentrations. Therefore, we have proposed that PARP inhibitors should be evaluated based both on catalytic PARP inhibition and PARP-DNA trapping. Here, we evaluated the novel PARP inhibitor, BMN 673, and compared its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically-modified chicken DT40 and human cancer cell lines. Although BMN 673, olaparib and rucaparib are comparable at inhibiting PARP catalytic activity, BMN 673 is ~100-fold more potent at trapping PARP-DNA complexes and more cytotoxic as single agent than olaparib, while olaparib and rucaparib show similar potencies in trapping PARP-DNA complexes. The high level of resistance of PARP1/2 knockout cells to BMN 673 demonstrates the selectivity of BMN 673 for PARP1/2. Moreover, we show that BMN 673 acts by stereospecific binding to PARP1 as its enantiomer, LT674, is several orders of magnitude less efficient. BMN 673 is also ~100-fold more cytotoxic than olaparib and rucaparib in combination with the DNA alkylating agents methyl methane sufonate (MMS) and temozolomide. Our study demonstrates that BMN 673 is the most potent clinical PARP inhibitor tested to date with the highest efficiency at trapping PARP-DNA complexes.