Journal Article

FZJ-2025-03035

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Exploring Arylidene–Indolinone Ligands of Autophagy Proteins LC3B and GABARAP

Leveille, A. N. ; Schwarzrock, T. ; Brown, H. ; True, B. ; Plasencia, J. ; Neudecker, P.FZJ* ; Üffing, A.FZJ* ; Weiergräber, O. H.FZJ* ; Willbold, D.FZJ* ; Kritzer, J. A. (Corresponding author)

2025
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acsmedchemlett.4c00517  doi:10.34734/FZJ-2025-03035

Abstract: We report the first structure–activity studies of arylidene–indolinone compound GW5074, which was reported as a ligand of autophagy-related protein LC3B. The literature has conflicting information on the binding affinity of this compound, and there is some debate regarding its use as a component of autophagy-dependent degrader compounds. We developed an AlphaScreen assay to measure competitive inhibition of the binding of known peptide ligands to LC3B and its paralog GABARAP. Eighteen analogs were synthesized and tested against both proteins. Inhibitory potencies were found to be in the mid- to high-micromolar range. 2D-NMR data revealed the binding site on GABARAP as hydrophobic pocket 1, where native peptide ligands bind with an aromatic side chain. Our results suggest that GW5074 binds LC3B and GABARAP with micromolar affinity. These affinities could support further exploration in targeted protein degradation, but only if off-target effects and poor solubility can be appropriately addressed.

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Contributing Institute(s):

1. Strukturbiochemie (IBI-7)

Research Program(s):

1. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)

Appears in the scientific report 2025

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Database coverage:
; ; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF < 5 ; Index Chemicus ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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