2. Academic Validation
  3. Inhibitors supercharge kinase turnover through native proteolytic circuits

Inhibitors supercharge kinase turnover through native proteolytic circuits

  • Nature. 2025 Nov 26. doi: 10.1038/s41586-025-09763-9.
Natalie S Scholes 1,  Martino Bertoni 2,  Arnau Comajuncosa-Creus 2,  Katharina Kladnik 1,  Xuefei Guo 3,  Fabian Frommelt 1,  Matthias Hinterndorfer 1 4,  Hlib Razumkov 5 6,  Polina Prokofeva 7,  Martin P Schwalm 8,  Florian Born 8,  Sandra Roehm 8,  Hana Imrichova 1,  Brianda L Santini 1,  Eleonora Barone 1,  Caroline Schätz 1,  Miquel Muñoz I Ordoño 1,  Severin Lechner 1,  Andrea Rukavina 1,  Iciar Serrano 1,  Miriam Abele 1,  Anna Koren 1,  Stefan Kubicek 1,  Stefan Knapp 8,  Nathanael S Gray 6 9,  Giulio Superti-Furga 1 10,  Bernhard Kuster 7 11 12,  Yigong Shi 13,  Patrick Aloy 2 14,  Georg E Winter 15 16
Affiliations

Affiliations

  • 1 CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 2 Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
  • 3 Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
  • 4 AITHYRA Research Institute for Biomedical Artificial Intelligence of the Austrian Academy of Sciences, Vienna, Austria.
  • 5 Department of Chemistry, Stanford School of Humanities and Sciences, Stanford University, Stanford, CA, USA.
  • 6 Department of Chemical and Systems Biology, ChEM-H, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
  • 7 Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany.
  • 8 Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt am Main, Germany.
  • 9 Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
  • 10 Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
  • 11 German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 12 Bavarian Biomolecular Mass Spectrometry Center (BayBioMS), Technical University of Munich, Freising, Germany.
  • 13 School of Life Sciences, Westlake University, Hangzhou, China.
  • 14 Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain.
  • 15 CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. gwinter@aithyra.at.
  • 16 AITHYRA Research Institute for Biomedical Artificial Intelligence of the Austrian Academy of Sciences, Vienna, Austria. gwinter@aithyra.at.
PMID: 41299171 DOI: 10.1038/s41586-025-09763-9
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 destabilization2-4. Among Others, this has repeatedly been observed for kinase inhibitors5-7. 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.

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