The use of small molecules to induce targeted protein degradation is increasingly growing in the drug discovery landscape, and protein degraders have progressed rapidly through the pipelines. Despite the advances made so far, their synthesis still represents a significant burden and new approaches are highly demanded. Herein we report an unprecedented platform that leverages the modular nature of both multicomponent reactions and degraders to enable the preparation of highly decorated PROTACs. As a proof of principle, our platform has been applied to the preparation of potential BRD4-degrading PROTACs, resulting in the discovery of a set of degraders endowed with high degradation efficiency. Compared to the existing methods, our approach offers a versatile and cost-effective means to access libraries of protein degraders and increase the chance of identifying successful candidates.

中文翻译：

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用于合成蛋白质降解剂的多功能且可持续的多组分平台：BRD4 降解 PROTAC 的概念验证应用


在药物发现领域，使用小分子诱导靶向蛋白质降解的情况越来越多，并且蛋白质降解剂在管道中取得了迅速进展。尽管迄今为止取得了进展，但它们的合成仍然是一个巨大的负担，并且迫切需要新的方法。在此，我们报告了一个前所未有的平台，该平台利用多组分反应和降解剂的模块化性质来制备高度装饰的 PROTAC。作为原理证明，我们的平台已应用于潜在的 BRD4 降解 PROTAC 的制备，从而发现了一组具有高降解效率的降解剂。与现有方法相比，我们的方法提供了一种通用且经济高效的方法来访问蛋白质降解剂库并增加识别成功候选者的机会。