Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Annu Rev Pharmacol Toxicol. 2012;52:57-78. doi: 10.1146/annurev-pharmtox-010611-134639. Epub 2011 Aug 2.
Identification of novel, validated targets remains a top priority in modern drug discovery. Chemical genetics represents a powerful approach to the discovery of new targets. Unlike the traditional target-based screen that relies on a predefined, sometimes poorly validated target, a chemical genetics-based phenotypic screen probes the entire molecular signaling pathway in an efficient and unbiased manner for the most drug-sensitive node. The most significant obstacle associated with this approach is identification of the efficacy targets of small-molecule probes. The huge potential of chemical genetics cannot be realized without the establishment of reliable mechanisms for target identification. In this article, we describe each essential element of the chemical genetics process, discuss common challenges that the field is facing, and critically review various biochemical and genetics approaches recently developed for target deconvolution. We also attempt to summarize lessons that we have collectively learned and provide a practical perspective to facilitate the advancement of chemical genetics.
鉴定新的、经过验证的靶点仍然是现代药物发现的首要任务。化学遗传学代表了发现新靶点的一种强大方法。与传统的基于靶点的筛选方法不同，后者依赖于预先定义的、有时验证效果不佳的靶点，基于化学遗传学的表型筛选以高效和无偏倚的方式探测整个分子信号通路，以找到对药物最敏感的节点。该方法最显著的障碍是确定小分子探针的疗效靶点。如果没有建立可靠的靶点鉴定机制，化学遗传学的巨大潜力就无法实现。本文描述了化学遗传学过程的每个基本要素，讨论了该领域面临的常见挑战，并批判性地回顾了最近为靶点剖析开发的各种生化和遗传学方法。我们还试图总结我们共同学到的经验教训，并提供一个实用的视角，以促进化学遗传学的发展。
