Lenalidomide Stabilizes Protein-Protein Complexes by Turning Labile Intermolecular H-Bonds into Robust Interactions

Targeted protein degradation is a promising therapeutic strategy, spearheaded by the anti-myeloma drugs lenalidomide , pomalidomide. These drugs stabilize very efficiently the complex between the E3 ligase Cereblon (CRBN) and several non-native client proteins (neo-substrates), including the transcription factors Ikaros and Aiolos and the enzyme Caseine Kinase 1 alpha (CK1 alpha,), resulting in their degradation. Although the structures for these complexes have been determined, there are no evident interactions that can account for the high efficiency of formation of the ternary complex. We show that lenalidomide's stabilization of the CRBN-CK1 alpha complex is largely due to hydrophobic shielding of intermolecular hydrogen bonds. We also find a quantitative relationship between hydrogen bond robustness and binding affinities of the ternary complexes. These results pave the way to further understand cooperativity effects in drug-induced protein-protein complexes and could help in the design of improved molecular glues and more efficient protein degraders.

Automated summary

Targeted protein degradation is a promising therapeutic strategy, and lenalidomide and pomalidomide are effective drugs in this field. These drugs stabilize the complex between CRBN and neo-substrates, leading to their degradation. The study identifies the role of hydrophobic shielding in stabilizing the CRBN-CK1 alpha complex and demonstrates the relationship between hydrogen bond robustness and binding affinities, providing insights for the design of improved protein degraders.