Eurofins Discovery, Burlingame, CA 94010, USA.
Cell Chem Biol. 2021 Mar 18;28(3):424-430. doi: 10.1016/j.chembiol.2021.01.010. Epub 2021 Feb 1.
Phenotypic drug discovery (PDD) uses biological systems directly for new drug screening. While PDD has proved effective in the discovery of drugs with novel mechanisms, for broader adoption, key challenges need resolution: progression of poorly qualified leads and overloaded pipelines due to lack of effective tools to process and prioritize hits; and advancement of leads with undesirable mechanisms that fail at more expensive stages of discovery. Here I discuss how human-based phenotypic platforms are being applied throughout the discovery process for hit triage and prioritization, for elimination of hits with unsuitable mechanisms, and for supporting clinical strategies through pathway-based decision frameworks. Harnessing the data generated in these platforms can also fuel a deeper understanding of drug efficacy and toxicity mechanisms. As these approaches increase in use, they will gain in power for driving better decisions, generating better leads faster and in turn promoting greater adoption of PDD.
表型药物发现（PDD）直接利用生物系统进行新药筛选。虽然 PDD 在发现具有新颖机制的药物方面已被证明是有效的，但为了更广泛地采用，仍需要解决以下关键挑战：由于缺乏有效的工具来处理和优先筛选命中化合物，导致不良先导化合物的进展和管道过载；以及具有不理想机制的先导化合物的推进，这些先导化合物在发现的更昂贵阶段失败。在这里，我将讨论如何在整个发现过程中应用基于人体的表型平台进行命中化合物的甄别和优先级排序，以消除具有不合适机制的命中化合物，并通过基于途径的决策框架支持临床策略。利用这些平台产生的数据也可以深入了解药物疗效和毒性机制。随着这些方法的应用越来越多，它们将更有能力做出更好的决策，更快地产生更好的先导化合物，并促进 PDD 的更广泛应用。
