David H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Res. 2011 Mar 1;71(5):1816-24. doi: 10.1158/0008-5472.CAN-10-2361. Epub 2011 Feb 22.
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 sensitizes BRCA-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.
小分子 DNA 修复抑制剂作为一种有效的抗癌疗法正在兴起，但是，涉及 DNA 修复过程的蛋白质网络非常庞大，这给有效候选药物的发现带来了障碍。为了解决这一挑战，我们使用了一种减法组合选择方法来鉴定一组与 DNA 修复复合物结合的肽配体。这些配体具有治疗潜力，我们的研究表明，一种选定的肽可以特异性结合并非竞争性地使 DNA-PKcs 失活，而 DNA-PKcs 是双链 DNA 断裂修复中至关重要的蛋白激酶。通过这种方式，该配体使 BRCA 缺陷型肿瘤细胞对遗传毒性治疗敏感。我们的研究结果为大规模平行筛选配体导向的 DNA 修复抑制剂建立了一个平台，这对癌症治疗具有直接的应用价值。
