ArticleRSC medicinal chemistry2023
Structural rationalization of GSPT1 and IKZF1 degradation by thalidomide molecular glue derivatives.
Article in RSC medicinal chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 38 citations in OpenAlex.
- Binding Modes of Thalidomide Derivatives in Cereblon-Neosubstrate Complexes Revealed by Molecular Dynamics and Free Energy Calculations.ACS omega · 2026Article
- Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues.Science (New York, N.Y.) · 2026Article
- Tipping the balance: synthesis and evaluation of centrinone-based degraders of polo-like kinase 4.RSC chemical biology · 2026Article
- Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells.ACS chemical biology · 2025Article
- The changing landscape of medicinal chemistry optimization.Nature reviews. Drug discovery · 2025Review
- Characterization of a dual degrader of MDM2 and GSPT1.European journal of medicinal chemistry · 2025Article
- Expanding the druggable zinc-finger proteome defines properties of drug-induced degradation.Molecular cell · 2025Article
- Property-Based Optimization of Cereblon-Based Molecular Glue Degraders.ACS medicinal chemistry letters · 2025Review
- Optimization and Evaluation of Complementary Degrader Discovery Assays for Application in Screening.ACS pharmacology & translational science · 2025Article
- High cereblon expression in neuroendocrine cancer confers vulnerability to GSPT1 molecular glue degrader.Experimental hematology & oncology · 2025Article
- Thalidomide-induced limb malformations: an update and reevaluation.Archives of toxicology · 2025Review
- Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.Journal of the American Chemical Society · 2024Article
- Article
- Asymmetric Dirhodium-Catalyzed Modification of Immunomodulatory Imide Drugs and Their Biological Assessment.ACS medicinal chemistry letters · 2024Article
- C2H2 Zinc Finger Transcription Factors Associated with Hemoglobinopathies.Journal of molecular biology · 2024Review
- Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells.bioRxiv : the preprint server for biology · 2024Article
- Development of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators.RSC medicinal chemistry · 2024Article
- Targeted protein degradation in CNS disorders: a promising route to novel therapeutics?Frontiers in molecular neuroscience · 2024Review
- Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead.RSC chemical biology · 2023Article
- Photoswitchable Molecular Glues Enable Optical Control of Transcription Factor Degradation.bioRxiv : the preprint server for biology · 2023Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Thalidomide and its derivatives are molecular glues that bind cereblon (CRBN), a component of an E3 ubiquitin ligase complex, and mediate protein interactions with neosubstrates resulting in their polyubiquitination and proteasomal degradation. The structural features of neosubstrate binding have been elucidated that highlight key interactions with a β-hairpin degron containing a glycine, which is present in a wide-range of proteins, including zinc-finger transcription factors such as IKZF1, and the translation termination factor GSPT1. Here, we profile 14 closely-related thalidomide derivatives in CRBN occupancy, and IKZF1 and GSPT1 degradation cell-based assays, and use crystal structures, computational docking and molecular dynamics to delineate subtle structure-activity relationships. Our findings will enable the rational design of CRBN modulators in the future, and help avoid the degradation of GSPT1 which is broadly cytotoxic.
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Registered trials
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.