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首页> 外文期刊>BMC Chemical Biology >Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue
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Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue

机译：新型合理设计的ATP竞争性嘌呤类似物对拓扑异构酶II的催化抑制作用

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Background: Topoisomerase II poisons are in clinical use as anti-cancer therapy for decades andwork by stabilizing the enzyme-induced DNA breaks. In contrast, catalytic inhibitors block theenzyme before DNA scission. Although several catalytic inhibitors of topoisomerase II have beendescribed, preclinical concepts for exploiting their anti-proliferative activity based on molecularcharacteristics of the tumor cell have only recently started to emerge. Topoisomerase II is anATPase and uses the energy derived from ATP hydrolysis to orchestrate the movement of theDNA double strands along the enzyme. Thus, interfering with ATPase function with low molecularweight inhibitors that target the nucleotide binding pocket should profoundly affect cells that arecommitted to undergo mitosis.Results: Here we describe the discovery and characterization of a novel purine diamine analogueas a potent ATP-competitive catalytic inhibitor of topoisomerase II. Quinoline aminopurinecompound 1 (QAP 1) inhibited topoisomerase II ATPase activity and decatenation reaction at sub-micromolar concentrations, targeted both topoisomerase II alpha and beta in cell free assays and,using a quantitative cell-based assay and a chromosome segregation assay, displayed catalyticenzyme inhibition in cells. In agreement with recent hypothesis, we show that BRCA1 mutantbreast cancer cells have increased sensitivity to QAP 1.Conclusion: The results obtained with QAP 1 demonstrate that potent and selective catalyticinhibition of human topoisomerase II function with an ATP-competitive inhibitor is feasible. Ourdata suggest that further drug discovery efforts on ATP-competitive catalytic inhibitors arewarranted and that such drugs could potentially be developed as anti-cancer therapy for tumorsthat bear the appropriate combination of molecular alterations.
机译：背景：拓扑异构酶II毒物在临床上已用作稳定数十年的抗癌疗法，并且通过稳定酶诱导的DNA断裂而起作用。相反，催化抑制剂在DNA断裂之前会阻断酶。尽管已经描述了拓扑异构酶II的几种催化抑制剂，但是基于肿瘤细胞的分子特性来利用它们的抗增殖活性的临床前概念才刚刚开始出现。拓扑异构酶II是一种ATP酶，它利用ATP水解产生的能量来协调DNA双链沿着酶的运动。因此，以靶向核苷酸结合袋的低分子量抑制剂干扰ATPase的功能应深刻影响承诺进行有丝分裂的细胞。结果：在此，我们描述了一种新型嘌呤二胺类似物的发现和表征，该类似物是一种强大的ATP竞争性拓扑异构酶催化抑制剂。二。喹啉氨基嘌呤化合物1（QAP 1）在亚微摩尔浓度下抑制拓扑异构酶II ATPase活性和脱级反应，在无细胞分析中同时靶向拓扑异构酶IIα和β，并使用基于细胞的定量分析和染色体分离分析显示了催化酶抑制作用在细胞中。与最新的假设相符，我们表明BRCA1突变型乳腺癌细胞对QAP 1的敏感性增加。结论：QAP 1获得的结果表明，利用ATP竞争性抑制剂对人拓扑异构酶II功能进行有效和选择性的催化抑制是可行的。我们的数据表明，需要进一步开发针对ATP竞争性催化抑制剂的药物，并且有可能将这种药物开发为具有适当分子改变组合的肿瘤的抗癌疗法。

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