Edinburgh Cancer Research UK Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh, UK.
Future Med Chem. 2012 Jan;4(1):87-105. doi: 10.4155/fmc.11.169.
Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of large chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' potency and selectivity profiles. However, high attrition of targeted agents in clinical development suggest that combinations of targeted agents will be most effective in treating solid tumors if the biological networks that permit cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and development strategies are suboptimal for the rational design and development of novel drug combinations. In this article, we highlight a series of emerging technologies supporting a less reductionist, more agile, drug-discovery and development approach for the rational design, validation, prioritization and clinical development of novel drug combinations.
当前的药物发现策略通常是“以靶标为中心”的，基于高通量筛选大型化学文库针对提名的靶标和具有优化的“靶标”效力和选择性特征的先导化合物的选择。然而，靶向药物在临床开发中的高淘汰率表明，如果能够识别并重新靶向允许癌细胞颠覆单药治疗的生物网络，那么靶向药物的组合将在治疗实体瘤方面最为有效。传统的药物发现和开发策略对于新型药物组合的合理设计和开发并不理想。在本文中，我们强调了一系列新兴技术，这些技术支持一种不那么简化、更灵活的药物发现和开发方法，用于新型药物组合的合理设计、验证、优先级排序和临床开发。
