Optimized Plk1 PBD Inhibitors Based on Poloxin Induce Mitotic Arrest and Apoptosis in Tumor Cells

详细信息    查看全文

• 作者：Andrej Scharow ; Monika Raab ; Krishna Saxena ; Sridhar Sreeramulu ; Denis Kudlinzki ; Santosh Gande ; Christina D枚tsch ; Elisabeth Kurunci-Csacsko ; Susan Klaeger ; Bernhard Kuster ; Harald Schwalbe ; Klaus Strebhardt ; Thorsten Berg
• 刊名：ACS Chemical Biology
• 出版年：2015
• 出版时间：November 20, 2015
• 年：2015
• 卷：10
• 期：11
• 页码：2570-2579
• 全文大小：624K
• ISSN：1554-8937

文摘

Polo-like kinase 1 (Plk1) is a central regulator of mitosis and has been validated as a target for antitumor therapy. The polo-box domain (PBD) of Plk1 regulates its kinase activity and mediates the subcellular localization of Plk1 and its interactions with a subset of its substrates. Functional inhibition of the Plk1 PBD by low-molecular weight inhibitors has been shown to represent a viable strategy by which to inhibit the enzyme, while avoiding selectivity issues caused by the conserved nature of the ATP binding site. Here, we report structure鈥揳ctivity relationships and mechanistic analysis for the first reported Plk1 PBD inhibitor, Poloxin. We present the identification of the optimized analog Poloxin-2, displaying significantly improved potency and selectivity over Poloxin. Poloxin-2 induces mitotic arrest and apoptosis in cultured human tumor cells at low micromolar concentrations, highlighting it as a valuable tool compound for exploring the function of the Plk1 PBD in living cells.