Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
Cell Chem Biol. 2016 Jan 21;23(1):3-9. doi: 10.1016/j.chembiol.2015.11.008.
The enthusiasm for phenotypic screening as an approach for small-molecule discovery has increased dramatically over the last several years. The recent increase in phenotype-based discoveries is in part due to advancements in phenotypic readouts in improved disease models that recapitulate clinically relevant biology in cell culture. Of course, a major historical barrier to using phenotypic assays in chemical biology has been the challenge in determining the mechanism of action (MoA) for compounds of interest. With the combination of medically inspired phenotypic screening and the development of modern MoA methods, we can now start implementing this approach in chemical probe and drug discovery. In this Perspective, we highlight recent advances in phenotypic readouts and MoA determination by discussing several case studies in which both activities were required for understanding the chemical biology involved and, in some cases, advancing toward clinical development.
近年来，表型筛选作为一种小分子发现方法的热情大幅增加。基于表型的发现最近有所增加，部分原因是在细胞培养中再现临床相关生物学的改进疾病模型中，表型读数得到了提高。当然，在化学生物学中使用表型测定法的一个主要历史障碍是确定感兴趣化合物的作用机制 (MoA) 的挑战。随着医学启发的表型筛选和现代 MoA 方法的发展，我们现在可以开始在化学探针和药物发现中实施这种方法。在本文观点中，我们通过讨论几个需要同时进行表型读数和 MoA 确定的案例研究，强调了这两个方面的最新进展，这些研究对于理解所涉及的化学生物学以及在某些情况下推进临床开发都是必需的。
