ArticleNature2016
Structural basis of lenalidomide-induced CK1α degradation by the CRL4(CRBN) ubiquitin ligase.
Article in Nature, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 312 papers.
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Who cites it
312 citing papers in PubMed, 582 citations in OpenAlex.
- Phase II Randomized Trial of Lenalidomide in Children With Pilocytic Astrocytomas and Optic Pathway Gliomas: A Report From the Children's Oncology Group.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2023Trial
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- From Ternary Modeling to Predictive PROTAC Design: A Computational Perspective.Journal of chemical information and modeling · 2026Article
- The synthetic landscape of cereblon (CRBN) binders: from thalidomide to emerging chemotypes.Chemical Society reviews · 2026Review
- Proteome-wide identification of the druggable CRBN interactome.Nature biotechnology · 2026Article
- Proteomics-Driven Strategies for Proximity-Inducing Drug Discovery.Angewandte Chemie (International ed. in English) · 2026Review
- In Silico Analysis of Enantioselective Binding of Pomalidomide Targets for Multiple Myeloma.Chirality · 2026Article
- Safety considerations for cereblon-recruiting targeted protein degraders.Nature reviews. Drug discovery · 2026Review
- Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies.Nature reviews. Drug discovery · 2026Review
- Binding Modes of Thalidomide Derivatives in Cereblon-Neosubstrate Complexes Revealed by Molecular Dynamics and Free Energy Calculations.ACS omega · 2026Article
- An Experimentally Validated Structure-Based Virtual Screening Approach to Identify Nucleotide-Binding Protein Inhibitors as a New Source of Kinase Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Mapping Scientific Landscapes and Therapeutic Innovations of Targeted Protein Degradation: A Scientometric Review.Pharmaceutics · 2026Review
- Induced ubiquitination of the partially disordered estrogen receptor alpha via a 14-3-3 directed molecular glue-PROTAC.Nature communications · 2026Article
- Article
252 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Thalidomide and its derivatives, lenalidomide and pomalidomide, are immune modulatory drugs (IMiDs) used in the treatment of haematologic malignancies. IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN (also known as CRL4(CRBN)) E3 ubiquitin ligase, and inhibit ubiquitination of endogenous CRL4(CRBN) substrates. Unexpectedly, IMiDs also repurpose the ligase to target new proteins for degradation. Lenalidomide induces degradation of the lymphoid transcription factors Ikaros and Aiolos (also known as IKZF1 and IKZF3), and casein kinase 1α (CK1α), which contributes to its clinical efficacy in the treatment of multiple myeloma and 5q-deletion associated myelodysplastic syndrome (del(5q) MDS), respectively. How lenalidomide alters the specificity of the ligase to degrade these proteins remains elusive. Here we present the 2.45 Å crystal structure of DDB1-CRBN bound to lenalidomide and CK1α. CRBN and lenalidomide jointly provide the binding interface for a CK1α β-hairpin-loop located in the kinase N-lobe. We show that CK1α binding to CRL4(CRBN) is strictly dependent on the presence of an IMiD. Binding of IKZF1 to CRBN similarly requires the compound and both, IKZF1 and CK1α, use a related binding mode. Our study provides a mechanistic explanation for the selective efficacy of lenalidomide in del(5q) MDS therapy. We anticipate that high-affinity protein-protein interactions induced by small molecules will provide opportunities for drug development, particularly for targeted protein degradation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.