Inhibitors supercharge kinase turnover through native proteolytic circuits

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 degradation<sup>1</sup>. Sporadic reports indicated that ligands designed to inhibit a target can also induce its destabilization<sup>2-4</sup>. Among others, this has repeatedly been observed for kinase inhibitors<sup>5-7</sup>. 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.

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Journal
Nature
Published
2025-11-26
DOI
https://doi.org/10.1038/s41586-025-09763-9
Citations
5
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
4.03
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article

Inhibitors supercharge kinase turnover through native proteolytic circuits

Georg E. Winter, Andrea Rukavina, Stefan Knapp, Patrick Aloy et al.
5 citations
Nature
Protein Degradation and Inhibitors
4.03
article

Inhibitors supercharge kinase turnover through native proteolytic circuits

Georg E. Winter, Andrea Rukavina, Stefan Knapp, Patrick Aloy, Miriam Abele, Arnau Comajuncosa-Creus, Nathanael S. Gray, Hlib Razumkov, Anna Koren, Martino Bertoni, Sandra Röhm, Severin Lechner, Fabian Frommelt, Polina Prokofeva, Martin P. Schwalm, Brianda L. Santini, Bernhard Küster, Hana Imrichová, Giulio Superti‐Furga, Natalie S. Scholes, Matthias Hinterndorfer, Stefan Kubicek, Eleonora Barone, Katharina Kladnik, Yigong Shi, Iciar Serrano, Xuefei Guo, Miquel Muñoz i Ordoño, Caroline Schätz, Florian Born
article en
5 citations

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 degradation<sup>1</sup>. Sporadic reports indicated that ligands designed to inhibit a target can also induce its destabilization<sup>2-4</sup>. Among others, this has repeatedly been observed for kinase inhibitors<sup>5-7</sup>. 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.

NatureVol. 649(8098)
Goethe University Frankfurt (DE), Institució Catalana de Recerca i Estudis Avançats (ES), Austrian Academy of Sciences (AT), Austrian Research Institute for Artificial Intelligence (AT), German Cancer Research Center (DE), Heidelberg University (DE), Westlake University (CN), Institute for Research in Biomedicine (ES), CeMM Research Center for Molecular Medicine (AT), Stanford Medicine (US), Center for Life Sciences (CN), Technical University of Munich (DE), Medical University of Vienna (AT), Stanford University (US), Tsinghua University (CN)
Openalex Percentile: Top 6%
Protein Degradation and Inhibitors
4.03
DOIOpen Access PDFOpenAlex
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