蛋白-蛋白相互作用:抗肿瘤药物研发的新方向

Protein-protein interaction: a novel direction for discovering anti-tumor drugs

肿瘤基因组学、靶向治疗和肿瘤生物学的研究进展明确了蛋白-蛋白相互作用(protein-protein interaction,PPI)在肿瘤发生发展中起着重要的作用,为抗肿瘤药物的研发提供了一个新的方向。然而,基于PPI的小分子药物研发面临着作用界面较大、结合口袋较浅等问题,使得基于PPI的药物开发极具挑战。近年来,PPI"热区"概念的提出,为基于PPI的小分子抑制剂的开发带来了新的思路。拟肽设计、片段筛选等药物发现策略的综合应用,丰富了PPI抑制剂开发的技术手段。由靶标验证(基于基因组学)、药物设计(基于PPI热区)以及临床研究(基于患者基因亚群)构成的三位一体开发模式逐步成形。可以预见,基于PPI的药物研发,将进一步促进肿瘤个体化医疗的发展。本文系统介绍了基于PPI发现抗肿瘤药物的方法,并对MDM2/p53,IAP,Bcl-2等热门靶标进行简要小结。

The progress of cancer genomics, targeted therapy and tumor biology has confirmed the important role of protein-protein interaction （PPI） in tumorigenesis, providing ano anti-tumor drugs. However, there are some challenges in the discovery of PPI shallow pockets. Recently, the theory of ＂hotspot＂ has been put forward, providi new tors an approach for developing such as large interface, nnovative method for the discovery of PPI inhibitors. The emerging drug design strategies, including peptidomimetic design and fragment- based screening, further enriched the technical means for discovery of PPI inhibitors. The target validation, drug design and clinical research together accelerate the development of PPI-based drug design, which will further promote the development of individualized medicine for oncotherapy. This review systematically illustrated the strategies for d p53, IAP and Bcl-2.