Small‐molecule stabilization of protein–protein interactions (PPIs) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a “bottom‐up” approach is largely unanswered. We report a novel concept for identifying initial chemical matter for PPI stabilization based on imine‐forming fragments. The imine bond offers a covalent anchor for site‐directed fragment targeting, whereas its transient nature enables efficient analysis of structure–activity relationships. This bond enables fragment identification and optimisation using protein crystallography. We report novel fragments that bind specifically to a lysine at the PPI interface of the p65‐subunit‐derived peptide of NF‐κB with the adapter protein 14‐3‐3. Those fragments that subsequently establish contacts with the p65‐derived peptide, rather than with 14‐3‐3, efficiently stabilize the 14‐3‐3/p65 complex and offer novel starting points for molecular glues.

中文翻译：

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通过基于亚胺的束缚的蛋白质-蛋白质相互作用的基于片段的稳定剂。

蛋白质间相互作用（PPI）的小分子稳定化在药物开发中是一个很有前途的概念，但是，如何以“自下而上”的方法识别或设计化学起始点的问题仍未得到解答。我们报告了一种新颖的概念，用于识别基于亚胺形成片段的PPI稳定化的初始化学物质。亚胺键为定点片段靶向提供了共价锚，而其瞬态性质则可以有效分析结构与活性之间的关系。该键可以使用蛋白质晶体学鉴定和优化片段。我们报道了新颖的片段，其特异性结合赖氨酸在NF-κB的p65亚基衍生肽的PPI界面上与衔接蛋白14-3-3。那些随后与p65衍生肽建立联系的片段，