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

Martin P. Schwalm, Johannes Dopfer, Adarsh Kumar, Francesco A. Greco, Nicolas Bauer, Frank Löhr, Jan Heering, Sara Cano-Franco, Severin Lechner, Thomas Hanke, Ivana Jaser, Viktoria Morasch, Christopher Lenz, Daren Fearon, Peter G. Marples, Charles W. E. Tomlinson, Lorene Brunello, Krishna Saxena, Nathan B. P. Adams, Frank von Delft, Susanne Müller, Alexandra Stolz, Ewgenij Proschak, Bernhard Kuster, Stefan Knapp () and Vladimir V. Rogov ()
Additional contact information
Martin P. Schwalm: Goethe University Frankfurt
Johannes Dopfer: Goethe University Frankfurt
Adarsh Kumar: Goethe University Frankfurt
Francesco A. Greco: Goethe University Frankfurt
Nicolas Bauer: Goethe University Frankfurt
Frank Löhr: Goethe University Frankfurt
Jan Heering: Theodor-Stern-Kai 7
Sara Cano-Franco: Goethe University
Severin Lechner: Technical University of Munich
Thomas Hanke: Goethe University Frankfurt
Ivana Jaser: NanoTemper Technologies GmbH
Viktoria Morasch: Goethe University Frankfurt
Christopher Lenz: Goethe University Frankfurt
Daren Fearon: Harwell Science and Innovation Campus
Peter G. Marples: Harwell Science and Innovation Campus
Charles W. E. Tomlinson: Harwell Science and Innovation Campus
Lorene Brunello: Goethe University
Krishna Saxena: Goethe University Frankfurt
Nathan B. P. Adams: NanoTemper Technologies GmbH
Frank von Delft: Harwell Science and Innovation Campus
Susanne Müller: Goethe University Frankfurt
Alexandra Stolz: Goethe University
Ewgenij Proschak: Goethe University Frankfurt
Bernhard Kuster: Technical University of Munich
Stefan Knapp: Goethe University Frankfurt
Vladimir V. Rogov: Goethe University Frankfurt

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54409-5

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