TY  - JOUR
AU  - Scholes, Natalie S
AU  - Bertoni, Martino
AU  - Comajuncosa-Creus, Arnau
AU  - Kladnik, Katharina
AU  - Guo, Xuefei
AU  - Frommelt, Fabian
AU  - Hinterndorfer, Matthias
AU  - Razumkov, Hlib
AU  - Prokofeva, Polina
AU  - Schwalm, Martin P
AU  - Born, Florian
AU  - Roehm, Sandra
AU  - Imrichova, Hana
AU  - Santini, Brianda L
AU  - Barone, Eleonora
AU  - Schätz, Caroline
AU  - Muñoz I Ordoño, Miquel
AU  - Lechner, Severin
AU  - Rukavina, Andrea
AU  - Serrano, Iciar
AU  - Abele, Miriam
AU  - Koren, Anna
AU  - Kubicek, Stefan
AU  - Knapp, Stefan
AU  - Gray, Nathanael S
AU  - Superti-Furga, Giulio
AU  - Kuster, Bernhard
AU  - Shi, Yigong
AU  - Aloy, Patrick
AU  - Winter, Georg E
TI  - Inhibitors supercharge kinase turnover through native proteolytic circuits.
JO  - Nature
VL  - nn
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2025-02631
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:41299171
DO  - DOI:10.1038/s41586-025-09763-9
UR  - https://inrepo02.dkfz.de/record/306592
ER  -