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@ARTICLE{Scholes:306592,
      author       = {N. S. Scholes and M. Bertoni and A. Comajuncosa-Creus and
                      K. Kladnik and X. Guo and F. Frommelt and M. Hinterndorfer
                      and H. Razumkov and P. Prokofeva and M. P. Schwalm and F.
                      Born and S. Roehm and H. Imrichova and B. L. Santini and E.
                      Barone and C. Schätz and M. Muñoz I Ordoño and S. Lechner
                      and A. Rukavina and I. Serrano and M. Abele and A. Koren and
                      S. Kubicek and S. Knapp and N. S. Gray and G. Superti-Furga
                      and B. Kuster$^*$ and Y. Shi and P. Aloy and G. E. Winter},
      title        = {{I}nhibitors supercharge kinase turnover through native
                      proteolytic circuits.},
      journal      = {Nature},
      volume       = {nn},
      issn         = {0028-0836},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2025-02631},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      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.},
      cin          = {MU01},
      ddc          = {500},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41299171},
      doi          = {10.1038/s41586-025-09763-9},
      url          = {https://inrepo02.dkfz.de/record/306592},
}