Department of Physiology, Anatomy, and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK.
Department of Physiology, Anatomy, and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK.
Trends Pharmacol Sci. 2024 Aug;45(8):723-738. doi: 10.1016/j.tips.2024.06.001. Epub 2024 Jul 15.
Before molecular pathways in cancer were known to a depth that could predict targets, drug development relied on phenotypic screening, where the effectiveness of candidate chemicals is judged from functional readouts without considering the mechanisms of action. The unraveling of tumor-specific pathways has brought targets for molecularly driven drug discovery, but precedents in the field have shown that awareness of pathways does not necessarily predict therapeutic efficacy, and many cancers still lack druggable targets. Phenotypic screening therefore retains a niche in drug development where a targeted approach is not informative. We analyze the unique advantages of phenotypic screens, and how technological advances have improved their discovery power. Notable advances include the use of larger biological panels and refined protocols that address the disease-relevance and increase data content with imaging and omic approaches.
在癌症的分子途径被深入了解到足以预测靶点之前，药物开发依赖于表型筛选，即不考虑作用机制，仅根据功能读数来判断候选化学物质的有效性。肿瘤特异性途径的阐明为分子驱动的药物发现带来了靶点，但该领域的先例表明，对途径的认识并不一定能预测治疗效果，而且许多癌症仍然缺乏可成药的靶点。因此，表型筛选在药物开发中仍然具有一定的地位，在这种情况下，靶向方法没有信息。我们分析了表型筛选的独特优势，以及技术进步如何提高它们的发现能力。值得注意的进展包括使用更大的生物面板和改进的方案，这些方案解决了疾病相关性问题，并通过成像和组学方法增加了数据含量。
