Targeting Cytotoxic Agents to Tumours through Small Molecule Covalent Binding

概述摘要选择性靶向肿瘤的强效细胞毒性剂的能力是非常有吸引力的，多年来一直是癌症研究的圣杯。我们正在开发使用共价抑制剂作为靶向剂将药物分子携带到肿瘤细胞的方法。一旦发生这种情况，随后的反应将触发连接的细胞毒性剂的释放。如果共价抑制剂的蛋白质靶标在肿瘤细胞中过表达，则细胞毒性剂将能够选择性地靶向这些细胞。我们预计，这将导致改善的癌细胞杀伤与潜在的副作用减少。在该项目中，我们将开发新的释放机制，使用模型系统优化这些机制，然后评估系统的潜力，发挥选择性抗肿瘤作用在细胞实验中。这些结果将被应用于开发一系列系统，使用不同的细胞毒性效应和靶向vehicle.ImpactThis工作将探索一种新的方法，选择性地将分子递送到肿瘤细胞。我们预计，从这方面获得的见解将导致新的癌症治疗方法与现有的协议的潜在优势。一般原则也适用于其他疾病领域和化学生物学应用中蛋白质的特异性靶向。

OverviewAbstractThe ability to target a potent cytotoxic agent selectively to a tumour is very attractive and has been a holy grail of cancer research for many years. We are developing methods that use covalent inhibitors as targeting agents to carry drug molecules to tumour cells. Once this occurs, a subsequent reaction will trigger release of a linked cytotoxic agent. Provided the protein target of the covalent inhibitor is overexpressed in tumour cell, the cytotoxic agent will be able to target these cells selectively. We anticipate that this will lead to improved cancer cell killing with the potential for reduced side effects.In the project we will develop new release mechanisms, optimize these mechanisms using model systems and then assess the potential of the systems to exert selective anti-tumour effects in cellular experiments. These results will then be applied to the development a range of systems using different cytotoxic effects and targeting vehicles.ImpactThis work will explore a new method of selective delivery of molecules to tumour cells. We anticipate that insights gained from this will lead to new approaches to cancer therapy with potential advantages over existing protocols. The general principle will also be applicable to specific targeting of proteins in other disease areas and in chemical biology applications.