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 and 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 1α (CK1α,), 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–CK1α 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.