Holvey Rhian S, Valkov Eugene, Neal David, Stewart Murray, Abell Chris
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK).
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH (UK).
ChemMedChem. 2015 Jul;10(7):1232-9. doi: 10.1002/cmdc.201500014. Epub 2015 Apr 20.
Protein-protein interactions are difficult therapeutic targets, and inhibiting pathologically relevant interactions without disrupting other essential ones presents an additional challenge. Herein we report how this might be achieved for the potential anticancer target, the TPX2-importin-α interaction. Importin-α is a nuclear transport protein that regulates the spindle assembly protein TPX2. It has two binding sites--major and minor-to which partners bind. Most nuclear transport cargoes use the major site, whereas TPX2 binds principally to the minor site. Fragment-based approaches were used to identify small molecules that bind importin-α, and crystallographic studies identified a lead series that was observed to bind specifically to the minor site, representing the first ligands specific for this site. Structure-guided synthesis informed the elaboration of these fragments to explore the source of ligand selectivity between the minor and major sites. These ligands are starting points for the development of inhibitors of this protein-protein interaction.
蛋白质-蛋白质相互作用是难以攻克的治疗靶点，而在不破坏其他重要相互作用的情况下抑制病理相关的相互作用更是一项额外的挑战。在此我们报告了针对潜在抗癌靶点TPX2-importin-α相互作用如何实现这一点。Importin-α是一种核转运蛋白，可调节纺锤体组装蛋白TPX2。它有两个结合位点——主要位点和次要位点——其伙伴会与之结合。大多数核转运货物使用主要位点，而TPX2主要与次要位点结合。基于片段的方法被用于识别与importin-α结合的小分子，晶体学研究确定了一个先导系列，观察到该系列特异性结合次要位点，代表了该位点的首个特异性配体。结构导向合成指导了这些片段的优化，以探索次要位点和主要位点之间配体选择性的来源。这些配体是开发这种蛋白质-蛋白质相互作用抑制剂的起点。
