下一代拓扑异构酶抑制剂:基本原理和生物标记策略。
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Teicher英航
下一代拓扑异构酶抑制剂:基本原理和生物标记策略。
生物化学杂志。2008年3月15日,75 (6):1262 - 71。Epub 2007年10月22日。
- PubMed ID
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18061144 (在PubMed]
- 文摘
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拓扑异构酶I (TopoI),一个重要的酶,产生一个DNA单链断裂允许DNA复制的放松。包括顺序transesterifcations酶机制。破损和关闭反应生成磷酸二酯债券和类似的自由能,所以自由反应是可逆的。TopoI反应中间由酶共价链接到DNA被称为“可分裂的复杂”。共价结合TopoI-DNA复合物可以恢复。喜树碱类似物,topotecan和伊立替康批准TopoI-targeted药物。都有局限性,由于喜树碱内酯和ring-opened形式之间的平衡。几个策略正在探索开发改进TopoI抑制剂。Homocamptothecins,新陈代谢不稳定喜树碱内酯被替换为一个更稳定的七人beta-hydroxylactone,强有力的抗癌药物。Gimatecan是seven-position修改的亲脂性的喜树碱开发提供快速吸收和积累在细胞和一个稳定的TopoI-DNA-drug三元复杂。 Diflomotecan, a homocamptothecin, and gimatecan are in Phase II clinical trial. Among non-camptothecins, edotecarin, an indolocarbazole that results in DNA C/T-G cleavage compared with T-G/A for camptothecins, is in Phase II clinical trial. Indenoisoquinolines were identified as TopoI inhibitors by the NCI 60-cell line COMPARE analysis. Co-crystal structures of two indenoisoquinolines with TopoI-DNA elucidated the structure of the ternary complex. Indenoisoquinolines are in preclinical development. Dibenzonaphthyridinone TopoI inhibitors have undergone extensive structure-activity examination. ARC-111 was selected for in-depth preclinical study. Biomarkers are under investigation to predict clinical efficacy from preclinical models, to allow determination of drug targeting in vivo and to aid selection of patients most likely to benefit from TopoI inhibitor therapy. gamma-H2AX formation may be a useful pharmacodynamic marker. A gene signature developed for topotecan sensitivity/resistance may have value in patient identification. Convergence of these efforts should result in clinically effective second generation TopoI inhibitors.