Discovery of DNA repair inhibitors by combinatorial library profiling.
Discovery of DNA repair inhibitors by combinatorial library profiling.
复制标题
通过组合文库分析发现 DNA 修复抑制剂。
DOI：
10.1158/0008-5472.can-10-2361
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发表时间：
2011
期刊：
影响因子：
11.2
通讯作者：
Arap,Wadih
中科院分区：
文献类型：
--
作者：
Moeller,BenjaminJ;Sidman,RichardL;Pasqualini,Renata;Arap,Wadih
Small molecule inhibitors of DNA repair are emerging as potent and selective anticancer therapies, but the sheer magnitude of the protein networks involved in DNA repair processes poses obstacles to discovery of effective candidate drugs. To address this challenge, we used a subtractive combinatorial selection approach to identify a panel of peptide ligands that bind DNA repair complexes. Supporting the concept that these ligands have therapeutic potential, we show that one selected peptide specifically binds and noncompetitively inactivates DNA-PKcs, a protein kinase critical in double-strand DNA break repair. In doing so, this ligand sensitizesBRCA-deficient tumor cells to genotoxic therapy. Our findings establish a platform for large-scale parallel screening for ligand-directed DNA repair inhibitors, with immediate applicability to cancer therapy.Cancer Res; 71(5); 1816–24. ©2011 AACR.
