The Rockefeller University, New York, NY 10065, USA.
Biochem J. 2011 Jan 15;433(2):e1-2. doi: 10.1042/BJ20102038.
More than 20 protein kinases are directly activated by 3-phosphoinositide-dependent kinase 1 (PDK1), which is a central component of the pathways that regulate cell growth, proliferation and survival. Despite the importance of PDK1 in cell signalling, highly selective PDK1 inhibitors have not been described. In this issue of the Biochemical Journal, Dario Alessi's group and their collaborators at GlaxoSmithKline report GSK2334470, a potent and selective PDK1 inhibitor. They show that this compound blocks the phosphorylation of known PDK1 substrates, but surprisingly find that the potency and kinetics of inhibition vary for different PDK1 targets. This substrate-specific inhibition has implications for the development of PDK1 inhibitors as drugs.
超过 20 种蛋白激酶可被 3-磷酸肌醇依赖性激酶 1（PDK1）直接激活，PDK1 是调节细胞生长、增殖和存活的途径中的一个核心组成部分。尽管 PDK1 在细胞信号转导中非常重要，但尚未描述出高度选择性的 PDK1 抑制剂。在本期《生物化学杂志》中，Dario Alessi 小组及其在葛兰素史克公司的合作者报告了 GSK2334470，这是一种有效的、选择性的 PDK1 抑制剂。他们表明，该化合物可阻断已知 PDK1 底物的磷酸化，但令人惊讶的是，他们发现不同 PDK1 靶标的抑制效力和动力学存在差异。这种底物特异性抑制对 PDK1 抑制剂作为药物的开发具有重要意义。
