ArticleJournal of medicinal chemistry2023
Lenalidomide Stabilizes Protein-Protein Complexes by Turning Labile Intermolecular H-Bonds into Robust Interactions.
Article in Journal of medicinal chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 28 citations in OpenAlex.
- Binding Modes of Thalidomide Derivatives in Cereblon-Neosubstrate Complexes Revealed by Molecular Dynamics and Free Energy Calculations.ACS omega · 2026Article
- Review
- Understanding the Role of H-Bonds in the Stability of Molecular Glue-Induced Ternary Complexes.Journal of chemical information and modeling · 2026Article
- Clues for glues: from serendipity to nature's blueprints in degrader discovery.Essays in biochemistry · 2025Review
- The Quasi-Bound State as a Predictor of Relative Binding Free Energy.Journal of chemical information and modeling · 2025Article
- Diversity Synthesis Using Glutarimides as Rhodium Carbene Precursors in Enantioselective C-H Functionalization and Cyclopropanation.Journal of the American Chemical Society · 2025Article
- Cullin-RING ligase BioE3 reveals molecular-glue-induced neosubstrates and rewiring of the endogenous Cereblon ubiquitome.Cell communication and signaling : CCS · 2025Article
- Mining Druggable Sites in Influenza A Hemagglutinin: Binding of the Pinanamine-Based Inhibitor M090.ACS medicinal chemistry letters · 2025Article
- Asymmetric Dirhodium-Catalyzed Modification of Immunomodulatory Imide Drugs and Their Biological Assessment.ACS medicinal chemistry letters · 2024Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
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