Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Oncogene. 2012 Apr 12;31(15):1938-48. doi: 10.1038/onc.2011.377. Epub 2011 Sep 5.
Survivin is a member of the inhibitor of apoptosis protein family and has an essential role in mitosis. Survivin is overexpressed in a large variety of human cancers and represents an attractive target for cancer therapy. Epidermal growth factor receptor and Her/neu-transformed human tumors in particular exhibit high levels of survivin. The survivin protein forms dimers through a conserved region that is critical for subcellular localization and biological functions of the protein. We identified small molecules that target a specific cavity adjacent to the survivin dimerization surfaces. S12, a lead compound identified in the screen, can bind to the survivin protein at the intended target site. Moreover, S12 alters spindle formation, causing mitotic arrest and cell death, and inhibits tumor growth in vitro and in vivo. Cell death occurs in premetaphase stage following mitotic arrest and is not a consequence of general toxicity. Thus, the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers.
生存素是凋亡抑制蛋白家族的一员，在有丝分裂中具有重要作用。生存素在多种人类癌症中过度表达，是癌症治疗的一个有吸引力的靶点。表皮生长因子受体和 Her/neu 转化的人类肿瘤尤其表现出高水平的生存素。生存素蛋白通过一个保守区域形成二聚体，该区域对蛋白的亚细胞定位和生物学功能至关重要。我们鉴定了靶向生存素二聚化表面附近特定腔的小分子。在筛选中发现的先导化合物 S12 可以在预期的靶位与生存素蛋白结合。此外，S12 改变纺锤体形成，导致有丝分裂阻滞和细胞死亡，并抑制体外和体内的肿瘤生长。有丝分裂阻滞后细胞死亡发生在前期阶段，不是一般毒性的结果。因此，该研究验证了生存素蛋白中的一个新的治疗靶点，并为开发一类治疗人类癌症的新型治疗性小分子提供了一个有前途的策略。
