Davis Rebecca K, Chellappan Srikumar
Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Drug News Perspect. 2008 Jul-Aug;21(6):331-5. doi: 10.1358/dnp.2008.21.6.1246832.
Cell-cycle progression in cancer is often mediated by disrupting the function of the retinoblastoma tumor suppressor protein, Rb. One way in which Rb's function is altered is through phosphorylation mediated by cyclin-dependent kinases (CDKs). Our studies have shown that the Raf-1 kinase binds and phosphorylates Rb very early in the cell cycle prior to the binding of cyclins and CDKs. It was also found that human lung cancer tumor samples had increased binding of Raf-1 to Rb, suggesting this interaction could have contributed to the malignancy of these tumors. Disrupting the Rb-Raf-1 interaction could inhibit cell proliferation in a multitude of cancer cell lines as well as prevent angiogenesis and tumor growth in vivo. Thus, the Rb-Raf-1 interaction is a promising therapeutic target for cancer. This review will highlight the importance of the Rb-Raf-1 interaction in cancer, the search for small molecules capable of disrupting the interaction as well as properties of Rb-Raf-1 disruptors, focusing specifically on RRD-251 (Rb-Raf-1 Disruptor 251). This review will also touch on why targeting protein-protein interactions may be a viable alternate and better strategy to inhibiting kinase function for cancer therapies.
癌症中的细胞周期进程通常是通过破坏视网膜母细胞瘤肿瘤抑制蛋白Rb的功能来介导的。改变Rb功能的一种方式是通过细胞周期蛋白依赖性激酶（CDK）介导的磷酸化作用。我们的研究表明，Raf-1激酶在细胞周期蛋白和CDK结合之前就很早地结合并磷酸化Rb。还发现人类肺癌肿瘤样本中Raf-1与Rb的结合增加，这表明这种相互作用可能促成了这些肿瘤的恶性发展。破坏Rb与Raf-1的相互作用可以抑制多种癌细胞系中的细胞增殖，并在体内阻止血管生成和肿瘤生长。因此，Rb与Raf-1的相互作用是一个很有前景的癌症治疗靶点。这篇综述将重点介绍Rb与Raf-1相互作用在癌症中的重要性、寻找能够破坏这种相互作用的小分子以及Rb-Raf-1破坏剂的特性，特别关注RRD-251（Rb-Raf-1破坏剂251）。这篇综述还将探讨为什么针对蛋白质-蛋白质相互作用可能是一种可行的替代策略，并且是比抑制激酶功能更好的癌症治疗策略。
