Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases. In contrast, weak PROTAC:target protein affinity can be stabilized by high-affinity target:PROTAC:ligase trimer interactions, leading to efficient degradation. This study highlights design guidelines for generating potent PROTACs as well as possibilities for degrading undruggable proteins immune to traditional small-molecule inhibitors.

中文翻译：

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PROTAC设计的教训，包括混合弹头的选择性降解

选择性抑制蛋白质功能是现代药物发现的主要目标。在这里，我们报道了以前被研究不足的小分子靶向靶向嵌合体（PROTACs）的益处，该嵌合体募集E3泛素连接酶来靶向蛋白的泛素化和随后的蛋白酶体介导的降解。使用结合> 50种激酶的混杂CRBN和VHL招募的PROTAC，我们显示只有一部分结合的靶标被降解。这种选择性的基础依赖于E3泛素连接酶与靶蛋白之间的蛋白质-蛋白质相互作用，如因与PROTAC招募的E3连接酶不稳定的三元复合物而不会降解的结合蛋白所说明的那样。相比之下，弱的PROTAC：目标蛋白亲和力可以通过高亲和力的target：PROTAC：ligase三聚体相互作用来稳定，导致有效降解。这项研究重点介绍了生成有效PROTAC的设计指南，以及降解对传统小分子抑制剂免疫的不可消耗蛋白质的可能性。