Determination of key functional structures of an amorphous VHL-based SMARCA2 PROTAC

Daria Torodii, Jacob B. Holmes, Manuel Cordova, Pinelopi Moutzouri, Lotte Beek, Fredrik Edfeldt, Erik Malmerberg, Stig D. Friis, Johan R. Johansson, Alexander G. Milbradt, Sten O. Nilsson Lill, Benjamin Malfait, Staffan Schantz () and Lyndon Emsley ()
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Daria Torodii: École Polytechnique Fédérale de Lausanne (EPFL)
Jacob B. Holmes: École Polytechnique Fédérale de Lausanne (EPFL)
Manuel Cordova: École Polytechnique Fédérale de Lausanne (EPFL)
Pinelopi Moutzouri: École Polytechnique Fédérale de Lausanne (EPFL)
Lotte Beek: AstraZeneca R&D
Fredrik Edfeldt: AstraZeneca
Erik Malmerberg: Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca
Stig D. Friis: Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca
Johan R. Johansson: Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca
Alexander G. Milbradt: AstraZeneca R&D
Sten O. Nilsson Lill: AstraZeneca
Benjamin Malfait: AstraZeneca
Staffan Schantz: AstraZeneca
Lyndon Emsley: École Polytechnique Fédérale de Lausanne (EPFL)

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Proteolysis targeting chimeras (PROTACs) enable degradation of disease-related proteins via E3 ligase recruitment. PROTACs often do not easily crystallize, and they are usually formulated in amorphous forms. Determining the key interactions that stabilize the solid drug forms is of high interest. Here, we determine the complete atomic-level structure of an amorphous Von Hippel-Lindau (VHL)-based SMARCA2 PROTAC (PROTAC 2) using nuclear magnetic resonance (NMR) crystallography. We find that PROTAC 2 is more disordered as compared to previously studied amorphous formulations, and that the three functional units of the molecule have distinct structural types. In contrast to smaller drug molecules, where intermolecular hydrogen bonding interactions were found to be the main stabilization mechanism for the amorphous solid form, for PROTAC 2 we postulate that, in analogy to glassy polymers, the main stabilization mechanism is the entropic contribution introduced by the overall flexibility, especially in the linker region of the molecule. We also note that the most populated conformations found in the amorphous form differ from those of bound PROTAC 2 in the ternary protein complex as determined via X-ray crystallography. Our results provide insight into key structural features that stabilize amorphous formulations, specifically for molecules that can target proteins previously considered undruggable.

Date: 2025
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DOI: 10.1038/s41467-025-65478-5

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