%0 Journal Article
%A Schwalm, Martin P
%A Lenz, Christopher
%A Saxena, Krishna
%A Klionsky, Daniel J
%A Proschak, Ewgenij
%A Knapp, Stefan
%T Biochemical investigation of LC3/GABARAP-ligand interaction as an important quality measure for LC3/GABARAP-targeting small molecules: addendum to the guidelines (4th edition).
%J Autophagy
%V 21
%N 9
%@ 1554-8627
%C Abingdon, Oxon
%I Taylor & Francis
%M DKFZ-2025-00952
%P 2069-2073
%D 2025
%Z ISSN 1554-8635 / 2025 Sep;21(9):2069-2073
%X Targeted protein degradation (TPD) represents a new therapeutic modality that allows the targeting of proteins that are considered undruggable by conventional small molecules. While TPD approaches via the ubiquitin-proteasome system are well established and validated, additional degradation pathways still require rigorous characterization. Here, we focus on macroautophagy/autophagy tethering compounds, a class of small molecules, designed to recruit cargo to LC3/GABARAP proteins for subsequent autophagosome-dependent degradation. We provide guidance for the biophysical and structural characterization of small molecule modulators for studying LC3/GABARAP-ligand interactions. In addition, we discuss potential limitations of autophagy-based TPD systems and emphasize the need for rigorous quality control in the development of LC3/GABARAP-targeting small molecules.Abbreviations: DSF: differential scanning fluorimetry; FP: fluorescence polarization; FRET: Förster/fluorescence resonance energy transfer; HTRF: homogeneous time-resolved fluorescence; ITC: isothermal titration calorimetry; LIR: LC3-interacting region; MGs: molecular glues; NMR: nuclear magnetic resonance; PROTACs: PROteolysis-TArgeting Chimeras; SPR: surface plasmon resonance; TPD: targeted protein degradation; TR-FRET: time-resolved Förster/fluorescence resonance energy transfer; UPS: ubiquitin-proteasome system.
%K ATTECs (Other)
%K AUTACs (Other)
%K Atg8 (Other)
%K GABARAP (Other)
%K LC3 (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40344429
%R 10.1080/15548627.2025.2498506
%U https://inrepo02.dkfz.de/record/301267