Exploring Arylidene-Indolinone Ligands of Autophagy Proteins LC3B and GABARAP.

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. 18 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

SUBMITTER: Leveille AN 

PROVIDER: S-EPMC11565829 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature