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@ARTICLE{Leveille:1044128,
author = {Leveille, Alexandria N. and Schwarzrock, Thomas and Brown,
Hawley and True, Bennett and Plasencia, Joanet and
Neudecker, Philipp and Üffing, Alina and Weiergräber,
Oliver H. and Willbold, Dieter and Kritzer, Joshua A.},
title = {{E}xploring {A}rylidene–{I}ndolinone {L}igands of
{A}utophagy {P}roteins {LC}3{B} and {GABARAP}},
journal = {ACS medicinal chemistry letters},
volume = {16},
number = {2},
issn = {1948-5875},
address = {Washington, DC},
publisher = {ACS},
reportid = {FZJ-2025-03035},
pages = {271 - 277},
year = {2025},
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.},
cin = {IBI-7},
ddc = {610},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {5241 - Molecular Information Processing in Cellular Systems
(POF4-524)},
pid = {G:(DE-HGF)POF4-5241},
typ = {PUB:(DE-HGF)16},
doi = {10.1021/acsmedchemlett.4c00517},
url = {https://juser.fz-juelich.de/record/1044128},
}