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000306592 1001_ $$00000-0002-1053-4079$$aScholes, Natalie S$$b0
000306592 245__ $$aInhibitors supercharge kinase turnover through native proteolytic circuits.
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000306592 500__ $$a2026 Jan;649(8098):1032-1041
000306592 520__ $$aTargeted 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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000306592 7001_ $$aBertoni, Martino$$b1
000306592 7001_ $$00000-0002-9633-7665$$aComajuncosa-Creus, Arnau$$b2
000306592 7001_ $$aKladnik, Katharina$$b3
000306592 7001_ $$00000-0001-7135-0954$$aGuo, Xuefei$$b4
000306592 7001_ $$00000-0003-3666-8005$$aFrommelt, Fabian$$b5
000306592 7001_ $$00000-0003-2435-4690$$aHinterndorfer, Matthias$$b6
000306592 7001_ $$00000-0001-6150-8172$$aRazumkov, Hlib$$b7
000306592 7001_ $$aProkofeva, Polina$$b8
000306592 7001_ $$00000-0002-1252-1829$$aSchwalm, Martin P$$b9
000306592 7001_ $$aBorn, Florian$$b10
000306592 7001_ $$00000-0003-3999-712X$$aRoehm, Sandra$$b11
000306592 7001_ $$00000-0003-0385-1823$$aImrichova, Hana$$b12
000306592 7001_ $$aSantini, Brianda L$$b13
000306592 7001_ $$00000-0002-4788-7070$$aBarone, Eleonora$$b14
000306592 7001_ $$aSchätz, Caroline$$b15
000306592 7001_ $$00009-0003-4391-6393$$aMuñoz I Ordoño, Miquel$$b16
000306592 7001_ $$aLechner, Severin$$b17
000306592 7001_ $$00000-0001-8254-9360$$aRukavina, Andrea$$b18
000306592 7001_ $$aSerrano, Iciar$$b19
000306592 7001_ $$00000-0003-0084-2999$$aAbele, Miriam$$b20
000306592 7001_ $$00000-0003-2528-4970$$aKoren, Anna$$b21
000306592 7001_ $$00000-0003-0855-8343$$aKubicek, Stefan$$b22
000306592 7001_ $$00000-0001-5995-6494$$aKnapp, Stefan$$b23
000306592 7001_ $$00000-0001-5354-7403$$aGray, Nathanael S$$b24
000306592 7001_ $$00000-0002-0570-1768$$aSuperti-Furga, Giulio$$b25
000306592 7001_ $$00000-0002-9094-1677$$aKuster, Bernhard$$b26
000306592 7001_ $$00000-0003-2030-168X$$aShi, Yigong$$b27
000306592 7001_ $$00000-0002-3557-0236$$aAloy, Patrick$$b28
000306592 7001_ $$00000-0001-6606-1437$$aWinter, Georg E$$b29
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