Identification of a ligand binding site represents the starting point for a structure-based drug development program. Lack of a binding site hampers the development of improved ligands that modulate the protein of interest. In this letter, we describe the development of chemical tools that will allow for elucidation of the Hsp90 C-terminal ligand binding site. Our strategy is based on the preparation of paramagnetic analogs of KU-596, an investigational new drug that is currently undergoing clinical trials for the treatment of neuropathy and interacts with the Hsp90 C-terminal domain. In particular, we report the design and synthesis of three novel paramagnetic analogs of KU-596, which will be used to obtain long range distances for NMR structural studies of Hsp90 in complex with C-terminal ligands.

配体结合位点的识别代表了基于结构的药物开发计划的起点。缺乏结合位点阻碍了调节目标蛋白质的改进配体的开发。在这封信中，我们描述了允许阐明 Hsp90 C 末端配体结合位点的化学工具的开发。我们的策略基于 KU-596 的顺磁性类似物的制备，KU-596 是一种研究性新药，目前正在进行治疗神经病变的临床试验，并与 Hsp90 C 末端结构域相互作用。特别是，我们报告了 KU-596 的三种新型顺磁性类似物的设计和合成，它们将用于获得长距离的 Hsp90 与 C 末端配体复合的 NMR 结构研究。