Synthetic Lethality Triggered by Combining Olaparib with BRCA2–Rad51 Disruptors,ACS Chemical Biology

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Synthetic Lethality Triggered by Combining Olaparib with BRCA2–Rad51 Disruptors
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-09-01 00:00:00 , DOI: 10.1021/acschembio.7b00707
Federico Falchi ₁ , Elisa Giacomini ₁ , Tiziana Masini ₁ , Nicolas Boutard ₁ , Lorenza Di Ianni ₂ , Marcella Manerba ₂ , Fulvia Farabegoli ₃ , Lara Rossini ₄ , Janet Robertson ₄ , Saverio Minucci _{5,

6} , Isabella Pallavicini ₅ , Giuseppina Di Stefano ₂ , Marinella Roberti ₃ , Roberto Pellicciari ₄ , Andrea Cavalli _{1,

3}

Affiliation

In BRCA2-defective cells, poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors can trigger synthetic lethality, as two independent DNA-repairing mechanisms are simultaneously impaired. Here, we have pharmacologically induced synthetic lethality, which was triggered by combining two different small organic molecules. When administered with a BRCA2–Rad51 disruptor in nonmutant cells, Olaparib showed anticancer activity comparable to that shown when administered alone in BRCA2-defective cells. This strategy could represent an innovative approach to anticancer drug discovery and could be extended to other synthetic lethality pathways.

中文翻译：

Olaparib与BRCA2–Rad51干扰物联合触发的合成致死性

在BRCA2缺陷细胞中，聚腺苷二磷酸（ADP）-核糖）聚合酶抑制剂可引发合成杀伤力，因为同时损害了两个独立的DNA修复机制。在这里，我们已经通过药理学诱导了合成杀伤力，这是通过将两个不同的有机小分子结合而触发的。与非突变细胞中的BRCA2-Rad51破坏剂一起使用时，奥拉帕里比的抗癌活性与在BRCA2缺陷细胞中单独使用时的抗癌活性相当。该策略可以代表一种创新的抗癌药物发现方法，并且可以扩展到其他合成杀伤性途径。

更新日期：2017-09-04

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