Wang Yao, Koay Yen Chin, McAlpine Shelli R
Department of Medicine, University of New South Wales, 2052, Australia.
School of Chemistry, University of New South Wales, Sydney, NSW, 2052, Australia.
ChemMedChem. 2017 Mar 7;12(5):353-357. doi: 10.1002/cmdc.201600595. Epub 2017 Feb 27.
Selectively inhibiting target proteins in cancer cells over normal cells is one of the most critical features of a successful protein inhibitor for clinical applications. By evaluating and comparing the impact of a clinical N-terminal heat shock protein 90 (Hsp90) inhibitor, AUY922 (luminespib), on Hsp90 inhibition-associated cellular events in cancer cells versus normal cells, we found that it produces similar phenotype characteristics in both cell types, indicating that AUY922 is not selective for targeting Hsp90 in tumor cells. By comparison, the C-terminal Hsp90 modulator SM258 suppresses cell proliferation, triggers apoptosis, regulates the expression of Hsp90-associated heat shock proteins, and enhances the degradation of Hsp90's client proteins preferentially in cancer cells over normal cells. Our findings support a new paradigm that AUY922 is not tumor selective, whereas SM258 is more selective and likely acts through an Hsp90-dependent mechanism.
与正常细胞相比，选择性抑制癌细胞中的靶蛋白是临床应用中成功的蛋白抑制剂的最关键特征之一。通过评估和比较临床N端热休克蛋白90（Hsp90）抑制剂AUY922（鲁米斯匹）对癌细胞与正常细胞中Hsp90抑制相关细胞事件的影响，我们发现它在两种细胞类型中产生相似的表型特征，这表明AUY922对肿瘤细胞中靶向Hsp90没有选择性。相比之下，C端Hsp90调节剂SM258优先在癌细胞而非正常细胞中抑制细胞增殖、触发凋亡、调节Hsp90相关热休克蛋白的表达，并增强Hsp90客户蛋白的降解。我们的研究结果支持了一种新的范式，即AUY922没有肿瘤选择性，而SM258更具选择性，并且可能通过一种Hsp90依赖性机制发挥作用。
