TY  - JOUR
AU  - Schwalm, Martin P
AU  - Lenz, Christopher
AU  - Saxena, Krishna
AU  - Klionsky, Daniel J
AU  - Proschak, Ewgenij
AU  - Knapp, Stefan
TI  - Biochemical investigation of LC3/GABARAP-ligand interaction as an important quality measure for LC3/GABARAP-targeting small molecules: addendum to the guidelines (4th edition).
JO  - Autophagy
VL  - 21
IS  - 9
SN  - 1554-8627
CY  - Abingdon, Oxon
PB  - Taylor & Francis
M1  - DKFZ-2025-00952
SP  - 2069-2073
PY  - 2025
N1  - ISSN 1554-8635 / 2025 Sep;21(9):2069-2073
AB  - 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.
KW  - ATTECs (Other)
KW  - AUTACs (Other)
KW  - Atg8 (Other)
KW  - GABARAP (Other)
KW  - LC3 (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40344429
DO  - DOI:10.1080/15548627.2025.2498506
UR  - https://inrepo02.dkfz.de/record/301267
ER  -