Lum Pek Yee, Armour Christopher D, Stepaniants Sergey B, Cavet Guy, Wolf Maria K, Butler J Scott, Hinshaw Jerald C, Garnier Philippe, Prestwich Glenn D, Leonardson Amy, Garrett-Engele Philip, Rush Christopher M, Bard Martin, Schimmack Greg, Phillips John W, Roberts Christopher J, Shoemaker Daniel D
Rosetta Inpharmatics LLC, a wholly-owned subsidiary of Merck & Co, Inc, 12040 115th Avenue NE, Kirkland, WA 98034, USA.
Cell. 2004 Jan 9;116(1):121-37. doi: 10.1016/s0092-8674(03)01035-3.
Modern medicine faces the challenge of developing safer and more effective therapies to treat human diseases. Many drugs currently in use were discovered without knowledge of their underlying molecular mechanisms. Understanding their biological targets and modes of action will be essential to design improved second-generation compounds. Here, we describe the use of a genome-wide pool of tagged heterozygotes to assess the cellular effects of 78 compounds in Saccharomyces cerevisiae. Specifically, lanosterol synthase in the sterol biosynthetic pathway was identified as a target of the antianginal drug molsidomine, which may explain its cholesterol-lowering effects. Further, the rRNA processing exosome was identified as a potential target of the cell growth inhibitor 5-fluorouracil. This genome-wide screen validated previously characterized targets or helped identify potentially new modes of action for over half of the compounds tested, providing proof of this principle for analyzing the modes of action of clinically relevant compounds.
现代医学面临着开发更安全、更有效疗法以治疗人类疾病的挑战。目前使用的许多药物在发现时并不清楚其潜在的分子机制。了解它们的生物学靶点和作用方式对于设计改进的第二代化合物至关重要。在此，我们描述了利用全基因组标记杂合子库来评估78种化合物在酿酒酵母中的细胞效应。具体而言，固醇生物合成途径中的羊毛甾醇合酶被确定为抗心绞痛药物吗多明的靶点，这可能解释了其降低胆固醇的作用。此外，核糖体RNA加工外切体被确定为细胞生长抑制剂5-氟尿嘧啶的潜在靶点。这种全基因组筛选验证了先前已表征的靶点，或有助于确定超过一半测试化合物潜在的新作用方式，为分析临床相关化合物的作用方式提供了这一原理的证据。
