下一代拓扑异构酶I抑制剂:原理和生物标志物策略。
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Teicher英航
下一代拓扑异构酶I抑制剂:原理和生物标志物策略。
生物化学药物学杂志，2008年3月15日;75(6):1262-71。Epub 2007 10月22日。
- PubMed ID
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18061144 (PubMed视图］
- 摘要
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拓扑异构酶I (TopoI)，一种必需的酶，产生DNA单链断裂，允许DNA松弛复制。酶的机制包括连续的酯交换作用。断裂和闭合反应产生磷酸二酯键和类似的自由能，因此反应是自由可逆的。TopoI反应中间体由与DNA共价连接的酶组成，称为“可切割复合体”。共价结合的TopoI-DNA复合物可以被回收。喜树碱类似物拓扑替康和伊立替康是批准的拓扑替康靶向药物。由于喜树碱内酯和环开形式之间的平衡，两者都有局限性。研究人员正在探索几种策略来开发改进的TopoI抑制剂。同喜树碱，其中代谢不稳定的喜树碱内酯被更稳定的七元β -羟基内酯取代，是有效的抗癌剂。Gimatecan是一种7位修饰的亲脂性喜树碱，用于在细胞中快速吸收和积累，是一种稳定的topoi - dna -药物三元复合物。 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.