2025年11月26日出版的《自然》杂志发表了科学家的一项最新研究成果。来自奥地利科学院的Georg E. Winter团队提出了抑制剂通过天然蛋白水解回路加速激酶的周转。

然而，该研究组缺乏对这些现象的频率、普遍性和机制基础的理解。为了解决这一知识差距，课题组研究人员在1570种激酶抑制剂的细胞扰动后生成了98种激酶的动态丰度谱，揭示了160种抑制剂诱导的激酶不稳定的选择性实例。易于降解的激酶经常被注释为HSP90客户，因此确认伴侣剥夺是不稳定的重要途径。

然而，对抑制剂诱导的LYN、BLK和RIPK2降解的详细研究揭示了一种不同的、共同的机制逻辑，即抑制剂通过诱导一种激酶状态发挥作用，这种激酶状态通过内源性降解机制更有效地清除。在机制上，效应可以通过配体诱导的细胞活性、定位或高阶组装的变化来表现，这些变化可能由直接靶标接合或网络效应触发。总的来说，他们的数据表明，抑制剂诱导的激酶降解是一种常见的事件，并且将内源性降解回路的增压作为经典的邻近诱导降解剂的替代方案。

据悉，靶向蛋白降解是一种依赖于小分子的药理学策略，如蛋白水解靶向嵌合体（PROTACs）或分子胶，它们诱导目标蛋白和E3泛素连接酶之间的接近，从而促进目标泛素化和蛋白酶体降解。零星的报道表明，设计用于抑制靶标的配体也可以诱导其不稳定。其中，这在激酶抑制剂中已被反复观察到。

附：英文原文

Title: Inhibitors supercharge kinase turnover through native proteolytic circuits

Author: Scholes, Natalie S., Bertoni, Martino, Comajuncosa-Creus, Arnau, Kladnik, Katharina, Guo, Xuefei, Frommelt, Fabian, Hinterndorfer, Matthias, Razumkov, Hlib, Prokofeva, Polina, Schwalm, Martin P., Born, Florian, Roehm, Sandra, Imrichova, Hana, Santini, Brianda L., Barone, Eleonora, Schtz, Caroline, Muoz i Ordoo, Miquel, Lechner, Severin, Rukavina, Andrea, Serrano, Iciar, Abele, Miriam, Koren, Anna, Kubicek, Stefan, Knapp, Stefan, Gray, Nathanael S., Superti-Furga, Giulio, Kuster, Bernhard, Shi, Yigong, Aloy, Patrick, Winter, Georg E.

Issue&Volume: 2025-11-26

Abstract: Targeted protein degradation is a pharmacological strategy that relies on small molecules such as proteolysis-targeting chimeras (PROTACs) or molecular glues, which induce proximity between a target protein and an E3 ubiquitin ligase to prompt target ubiquitination and proteasomal degradation1. Sporadic reports indicated that ligands designed to inhibit a target can also induce its destabilization2,3,4. Among others, this has repeatedly been observed for kinase inhibitors5,6,7. However, we lack an understanding of the frequency, generalizability and mechanistic underpinnings of these phenomena. Here, to address this knowledge gap, we generated dynamic abundance profiles of 98 kinases after cellular perturbations with 1,570 kinase inhibitors, revealing 160 selective instances of inhibitor-induced kinase destabilization. Kinases prone to degradation are frequently annotated as HSP90 clients, therefore affirming chaperone deprivation as an important route of destabilization. However, detailed investigation of inhibitor-induced degradation of LYN, BLK and RIPK2 revealed a differentiated, common mechanistic logic whereby inhibitors function by inducing a kinase state that is more efficiently cleared by endogenous degradation mechanisms. Mechanistically, effects can manifest by ligand-induced changes in cellular activity, localization or higher-order assemblies, which may be triggered by direct target engagement or network effects. Collectively, our data suggest that inhibitor-induced kinase degradation is a common event and positions supercharging of endogenous degradation circuits as an alternative to classical proximity-inducing degraders.

DOI: 10.1038/s41586-025-09763-9

Source: https://www.nature.com/articles/s41586-025-09763-9