Wendt Michael D, Sun Chaohong, Kunzer Aaron, Sauer Daryl, Sarris Kathy, Hoff Ethan, Yu Liping, Nettesheim David G, Chen Jun, Jin Sha, Comess Kenneth M, Fan Yihong, Anderson Steven N, Isaac Binumol, Olejniczak Edward T, Hajduk Philip J, Rosenberg Saul H, Elmore Steven W
Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA.
Bioorg Med Chem Lett. 2007 Jun 1;17(11):3122-9. doi: 10.1016/j.bmcl.2007.03.042. Epub 2007 Mar 16.
Survivin is one of the most tumor-specific genes in the human genome and is an attractive target for cancer therapy. However, small-molecule ligands for survivin have not yet been described. Thus, an interrogation of survivin which could potentially both validate a small-molecule therapy approach, and determine the biochemical nature of any of survivin's functions has not been possible. Here we describe the discovery and characterization of a small molecule binding site on the survivin surface distinct from the Smac peptide-binding site. The new site is located at the dimer interface and exhibits many of the features of highly druggable, biologically relevant protein binding sites. A variety of small hydrophobic compounds were found that bind with moderate affinity to this binding site, from which one lead was developed into a group of compounds with nanomolar affinity. Additionally, a subset of these compounds are adequately water-soluble and cell-permeable. Thus, the structural studies and small molecules described here provide tools that can be used to probe the biochemical role(s) of survivin, and may ultimately serve as a basis for the development of small molecule therapeutics acting via direct or allosteric disruption of binding events related to this poorly understood target.
生存素是人类基因组中最具肿瘤特异性的基因之一，是癌症治疗的一个有吸引力的靶点。然而，尚未有关于生存素的小分子配体的报道。因此，对生存素进行研究，既可能验证小分子治疗方法，又能确定生存素任何功能的生化性质，这是不可能的。在此，我们描述了在生存素表面发现的一个与Smac肽结合位点不同的小分子结合位点，并对其进行了表征。新位点位于二聚体界面，具有许多高度可成药、与生物学相关的蛋白质结合位点的特征。发现了多种小的疏水化合物，它们以中等亲和力结合到这个结合位点，从中开发出一种先导化合物，进而得到一组具有纳摩尔亲和力的化合物。此外，这些化合物的一个子集具有足够的水溶性和细胞渗透性。因此，本文所述的结构研究和小分子提供了可用于探究生存素生化作用的工具，并最终可能作为开发通过直接或变构破坏与这个了解甚少的靶点相关的结合事件而起作用的小分子疗法的基础。
