Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, UK.
Drug Discov Today. 2012 Mar;17(5-6):203-14. doi: 10.1016/j.drudis.2012.02.002.
Conventional drug discovery strategies are typically 'target centric' based on the selection of lead compounds with optimised 'on-target' potency and selectivity profiles. However, high-attrition rates are often the result of compensatory or redundant cancer mechanisms and the fact that tumours do not find it difficult to escape inhibition of a single pathway. In this article, we highlight two emerging and complimentary technologies; namely phenotypic imaging and post-translational pathway profiling, which when combined with relevant disease models can provide pharmacodiagnostic and drug combination strategies that predict and counteract inherent and adaptive drug resistance. The implementation of such approaches at early stages of the drug discovery process enables more informed decisions on candidate drug selection and how to maximise and predict efficacy before clinical development.
传统的药物发现策略通常是基于选择具有优化“靶标”效力和选择性特征的先导化合物的“以靶标为中心”。然而,高淘汰率通常是由于补偿性或冗余的癌症机制以及肿瘤不难逃避单一途径抑制的事实造成的。在本文中,我们强调了两种新兴的互补技术;即表型成像和翻译后途径分析,当与相关疾病模型结合使用时,可以提供药物诊断和药物组合策略,预测和对抗固有和适应性耐药性。在药物发现过程的早期阶段实施这些方法,可以更明智地决策候选药物的选择,以及如何在临床开发之前最大化和预测疗效。