A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations.
A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations.
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DOI：
10.1038/nsmb.2076
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发表时间：
2011-06
影响因子：
16.8
通讯作者：
Fernandez-Capetillo O
中科院分区：
文献类型：
--
作者：
Toledo LI;Murga M;Zur R;Soria R;Rodriguez A;Martinez S;Oyarzabal J;Pastor J;Bischoff JR;Fernandez-Capetillo O
癌基因激活已被证明会产生复制出生的DNA损伤，也称为复制应激（RS）。值得注意的是，ATR激酶-而不是ATM-是RS的主要应答者。ATR研究的一个限制是缺乏有效的抑制剂。我们在这里描述了一个基于细胞的筛选策略，使我们能够确定化合物的ATR抑制活性在纳摩尔范围内。ATR的药理学抑制产生RS，在存在使复制叉停滞的条件下导致染色体断裂。此外，ATR抑制对p53缺陷细胞特别有毒，这种毒性被RS产生条件如细胞周期蛋白E的过表达所加剧。重要的是，其中一种化合物是NVP-BEZ 235，这是一种PI 3 K/mTOR双重抑制剂，目前正在测试癌症化疗，但我们现在发现它对ATM，ATR和DNA-PKcs也非常有效。
Oncogene activation has been shown to generate replication-born DNA damage, also known as replicative stress (RS). Notably, the ATR kinase –and not ATM- is the primary responder to RS. One limitation for the study of ATR is the lack of potent inhibitors. We here describe a cell-based screening strategy that has allowed us to identify compounds with ATR inhibitory activity in the nanomolar range. Pharmacological inhibition of ATR generates RS, leading to chromosomal breakage in the presence of conditions that stall replication forks. Moreover, ATR inhibition is particularly toxic for p53 deficient cells, this toxicity being exacerbated by RS-generating conditions such as the overexpression of cyclin E. Importantly, one of the compounds is NVP-BEZ235, a dual PI3K/mTOR inhibitor that is currently being tested for cancer chemotherapy, but which we now show is also very potent against ATM, ATR and DNA-PKcs.