DNA Minor Groove-Targeting Anticancer Agents

DNA 小沟靶向抗癌药物

• 批准号: 6867368
• 负责人: Daniel S Pilch
• 金额: $ 25.85万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867368
• 关键词: DNA damage; DNA topoisomerases; antineoplastics; benzimidazoles; chemical cleavage; chemical kinetics; cytotoxicity; drug design /synthesis /production; enzyme complex; intermolecular interaction; model design /development; molecular dynamics; molecular genetics; neoplasm /cancer chemotherapy; nucleic acid sequence; nucleic acid structure; oligonucleotides; physical model

DESCRIPTION (provided by applicant): Human DNA topoisomerase 1 (TOP1) has been established as an effective new molecular target for anticancer drugs. These agents inhibit (poison) TOP1 by trapping the covalent enzyme-DNA intermediate (termed the cleavable complex), thereby stimulating protein-linked DNA strand breaks, which represent a new form of DNA damage that effectively kills tumor cells. Terbenzimidazoles (TBs) represent a new structural class of TOP1 poisoning agents that bind in the minor groove of DNA. Select TB derivatives exhibit potent TOP1 poisoning activities and cytotoxicities exceeding that of the clinical camptothecin derivative, topotecan. However, the specific molecular interactions that govern the TOP1 poisoning and cytotoxic activities of the TBs are still poorly understood. The overall goal of this proposal is to develop the TBs as effective anticancer agents. Toward this goal, we will employ a broad range of computational, biophysical, biochemical, and cellular techniques to achieve the following specific aims: (i) Determine the TOP1-targeting specificity as well as the TOP1-mediated cytotoxicity of TB derivatives. These studies are designed to evaluate the potencies of the TBs at trapping TOP1-DNA cleavable complexes in intact cells as well as to establish their TOP1-directed cytotoxicities. (ii) Define the specific drug-enzyme and drug-DNA interactions that stabilize the ternary TB-DNA-TOP1 cleavable complex. We will use computational techniques in conjunction with available crystallographic information to generate explicitly solvated structural models of ternary TB-DNA-TOP1 cleavable complexes, and experimentally assess the validities and predictive integrities of our generated models. (iii) Enhance the TOP1 poisoning and cytotoxic efficacies of the TBs by reducing their propensities for self-association. In addition to the development of compounds with increased efficacy, these structure-activity studies will also result in compounds with enhanced water solubilities, a feature that has enormous potential value with regard to the ease of drug delivery. (iv) Determine the role of DNA minor groove binding in the poisoning of TOP1 by TBs. These studies are designed to enhance our understanding of the molecular mechanism by which the TBs poison TOP1. The information gleaned from our proposed studies will enable us to develop a rational approach to the design and development of next generation TB compounds that exhibit predictably enhanced TOP1 poisoning and cytotoxic activities.

描述（由申请人提供）：已确定人DNA拓扑异构酶1（TOP1）是抗癌药物的有效新分子靶标。这些药物通过捕获共价酶-DNA中间体（称为可切除的复合物），从而抑制（毒）TOP1，从而刺激蛋白质连接的DNA链断裂，这代表了有效杀死肿瘤细胞的新形式的DNA损伤。 Terbenzimidazoles（TBS）代表了一种新的TOP1中毒剂的新结构类别，它们结合了DNA的小凹槽。选择的结核病衍生物表现出有效的TOP1中毒活性和超过临床凸轮刺素衍生物Topotecan的细胞毒性。但是，控制TBS的TOP1中毒和细胞毒性活性的特定分子相互作用仍然很少了解。该提案的总体目标是将TBs开发为有效的抗癌剂。为了实现这一目标，我们将采用广泛的计算，生物物理，生化和细胞技术来实现以下特定目的：（i）确定TB衍生物的TOP1靶向特异性以及TOP1介导的细胞毒性。这些研究旨在评估TBS在完整细胞中捕获Top1-DNA可裂解复合物以及建立其TOP1指导的细胞毒性时的效力。 （ii）定义特定的药物 - 酶和药物-DNA相互作用，这些相互作用稳定了三元TB-DNA-TOP1可裂解的复合物。我们将使用与可用晶体学信息结合使用的计算技术来生成三元TB-DNA-TOP1可裂解复合物的明确溶剂化结构模型，并通过实验评估我们生成的模型的有效性和预测性完整性。 （iii）通过降低其自我关联的倾向来增强TBS的TOP1中毒和细胞毒性效率。除了发育具有提高功效的化合物外，这些结构活性研究还将导致水溶性增强的化合物，这一特征在药物递送方面具有巨大的潜在价值。 （iv）确定DNA小凹槽结合在TBS中的TOP1中毒中的作用。这些研究旨在增强我们对TBS毒药TOP1的分子机制的理解。从我们提出的研究中收集的信息将使我们能够开发出一种合理的方法来设计和开发下一代结核化合物，这些化合物可以预见地增强了TOP1中毒和细胞毒性活性。