Human Cancer Biobank Center, University of Ioannina, Ioannina, GR-45110, Greece.
Molecules. 2011 May 27;16(6):4408-27. doi: 10.3390/molecules16064408.
We are currently witnessing a decline in the development of efficient new anticancer drugs, despite the salient efforts made on all fronts of cancer drug discovery. This trend presumably relates to the substantial heterogeneity and the inherent biological complexity of cancer, which hinder drug development success. Protein-protein interactions (PPIs) are key players in numerous cellular processes and aberrant interruption of this complex network provides a basis for various disease states, including cancer. Thus, it is now believed that cancer drug discovery, in addition to the design of single-targeted bioactive compounds, should also incorporate diversity-oriented synthesis (DOS) and other combinatorial strategies in order to exploit the ability of multi-functional scaffolds to modulate multiple protein-protein interactions (biological hubs). Throughout the review, we highlight the chemistry driven approaches to access diversity space for the discovery of small molecules that disrupt oncogenic PPIs, namely the p53-Mdm2, Bcl-2/Bcl-xL-BH3, Myc-Max, and p53-Mdmx/Mdm2 interactions.
目前，尽管在癌症药物研发的各个方面都做出了显著努力，但高效的新型抗癌药物的开发仍在减少。这种趋势可能与癌症的巨大异质性和固有生物学复杂性有关，这些因素阻碍了药物开发的成功。蛋白质-蛋白质相互作用（PPIs）是许多细胞过程中的关键参与者，而这种复杂网络的异常中断为包括癌症在内的各种疾病状态提供了基础。因此，现在人们认为，癌症药物发现除了设计单靶标生物活性化合物外，还应该结合多样性导向合成（DOS）和其他组合策略，以利用多功能支架调节多个蛋白质-蛋白质相互作用（生物枢纽）的能力。在整篇综述中，我们强调了化学驱动的方法，以获得小分子的多样性空间，这些小分子可以破坏致癌性的 PPI，即 p53-Mdm2、Bcl-2/Bcl-xL-BH3、Myc-Max 和 p53-Mdmx/Mdm2 相互作用。
