Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets

Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome. In this work, we rigorously tested the target engagement of the reported ATTECs to validate the existing LC3/GABARAP ligands. Surprisingly, we were unable to detect interaction with their designated target LC3 using a diversity of biophysical methods. Intrigued by the idea of developing ATTECs, we evaluated the ligandability of LC3/GABARAP by in silico docking and large-scale crystallographic fragment screening. Data based on approximately 1000 crystal structures revealed that most fragments bound to the HP2 but not to the HP1 pocket within the LIR docking site, suggesting a favorable ligandability of HP2. Through this study, we identified diverse validated LC3/GABARAP ligands and fragments as starting points for chemical probe and ATTEC development.

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Publication Details

Journal
Nature Communications
Published
2024-11-25
DOI
https://doi.org/10.1038/s41467-024-54409-5
Citations
15
Primary Topic
Neuroscience and Neuropharmacology Research
Type
article
Field-Weighted Citation Impact
4.02

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article

Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets

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Neuroscience and Neuropharmacology Research
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article

Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets

Sara Cano-Franco, Ewgenij Proschak, Frank Löhr, Charles W.E. Tomlinson, Stefan Knapp, Krishna Saxena, Jan Heering, Christopher Lenz, Nicolas Bauer, Nathan B. P. Adams, Vladimir V. Rogov, Viktoria Morasch, Severin Lechner, Martin P. Schwalm, F. von Delft, Bernhard Küster, Susanne Müller, Lorène Brunello, Thomas Hanke, Adarsh Kumar, D. Fearon, Alexandra Stolz, Peter Marples, Johannes Dopfer, Francesco Greco, Ivana Jaser
article en
15 citations

Abstract

Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome. In this work, we rigorously tested the target engagement of the reported ATTECs to validate the existing LC3/GABARAP ligands. Surprisingly, we were unable to detect interaction with their designated target LC3 using a diversity of biophysical methods. Intrigued by the idea of developing ATTECs, we evaluated the ligandability of LC3/GABARAP by in silico docking and large-scale crystallographic fragment screening. Data based on approximately 1000 crystal structures revealed that most fragments bound to the HP2 but not to the HP1 pocket within the LIR docking site, suggesting a favorable ligandability of HP2. Through this study, we identified diverse validated LC3/GABARAP ligands and fragments as starting points for chemical probe and ATTEC development.

Nature CommunicationsVol. 15(1)
Goethe University Frankfurt (DE), German Cancer Research Center (DE), Heidelberg University (DE), Frankfurt Institute for Advanced Studies (DE), Diamond Light Source (GB), German Cancer Society (DE), Fraunhofer Institute for Translational Medicine and Pharmacology (DE), NanoTemper Technologies (Germany) (DE), Technical University of Munich (DE)
Bristol-Myers Squibb, Pfizer, Bayer, McGill University, Deutsches Krebsforschungszentrum, Genome Canada, Merck KGaA, Diamond Light Source, Ontario Genomics, European Federation of Pharmaceutical Industries and Associations, Ontario Genomics Institute, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Deutschen Konsortium für Translationale Krebsforschung, Genentech
Openalex Percentile: Top 5%
Neuroscience and Neuropharmacology Research
4.02
DOIOpen Access PDFOpenAlex
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