Zhang Zhiqiang, Abreu Barbara, Brothwood Jessica L, Alexander John, Sims Martin J, Lyons John F, Munck Joanne M, Hindley Christopher J
Astex Pharmaceuticals, Cambridge, UK.
Wellcome Sanger Institute, Hinxton, UK.
Commun Biol. 2025 Apr 24;8(1):656. doi: 10.1038/s42003-025-07966-4.
CRISPR tiling screen is a powerful tool to identify protein regions relevant to its biological function. Understanding the functional relevance of the regions of target protein is of great help for structure-based drug discovery. Studying the drug resistance mechanisms of small-molecule inhibitors is important for the development and clinical application of the compounds. Using MEK1 and MEK inhibitors as example here, we demonstrate the utility of CRISPR tiling to identify regions essential for cancer cell viability and regions where mutations are resistant to MEK inhibitors. We study the drug resistance mechanisms of the regions and discussed the potential, as well as limitations, of applying the technology to drug development. Our findings demonstrate the value and prompt the utilization of CRISPR tiling technology in structure-based drug discovery.
CRISPR 平铺筛选是一种识别与其生物学功能相关蛋白质区域的强大工具。了解靶蛋白区域的功能相关性对基于结构的药物发现有很大帮助。研究小分子抑制剂的耐药机制对化合物的开发和临床应用很重要。在此以MEK1和MEK抑制剂为例，我们展示了CRISPR平铺筛选在识别癌细胞生存能力所必需区域以及对MEK抑制剂耐药的突变区域方面的实用性。我们研究了这些区域的耐药机制，并讨论了将该技术应用于药物开发的潜力和局限性。我们的研究结果证明了CRISPR平铺筛选技术在基于结构的药物发现中的价值，并促使其得到应用。
