Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center , New York, New York 10021, United States.
J Med Chem. 2014 Feb 27;57(4):1208-24. doi: 10.1021/jm401552y. Epub 2014 Feb 18.
The discovery and development of heat shock protein 70 (Hsp70) inhibitors is currently a hot topic in cancer. In the preceding paper in this issue ( 10.1021/jm401551n ), we have described structure-activity relationship studies in the first Hsp70 inhibitor class rationally designed to bind to a novel allosteric pocket located in the N-terminal domain of the protein. These ligands contained an acrylamide to take advantage of an active cysteine embedded in the allosteric pocket and acted as covalent protein modifiers upon binding. Here, we perform chemical modifications around the irreversible inhibitor scaffold to demonstrate that covalent modification is not a requirement for activity within this class of compounds. The study identifies derivative 27c, which mimics the biological effects of the irreversible inhibitors at comparable concentrations. Collectively, the back-to-back manuscripts describe the first pharmacophores that favorably and selectively interact with a never explored pocket in Hsp70 and provide a novel blueprint for a cancer-oriented development of Hsp70-directed ligands.
热休克蛋白 70（Hsp70）抑制剂的发现和开发目前是癌症研究的一个热点。在本期杂志的前一篇论文中（10.1021/jm401551n），我们描述了首次合理设计的 Hsp70 抑制剂类别的结构-活性关系研究，这些抑制剂类别的设计旨在结合位于蛋白质 N 端结构域的新型别构口袋。这些配体含有丙烯酰胺，以利用别构口袋中嵌入的活性半胱氨酸，并在结合时充当共价蛋白质修饰剂。在这里，我们围绕不可逆抑制剂支架进行化学修饰，以证明共价修饰不是此类化合物活性的必需条件。该研究确定了衍生物 27c，它在可比浓度下模拟不可逆抑制剂的生物学效应。这两篇连续的论文共同描述了第一个与 Hsp70 中从未探索过的口袋有利且选择性相互作用的药效团，并为面向癌症的 Hsp70 导向配体的开发提供了新的蓝图。
