ArticleScience advances2021
Identification and optimization of molecular glue compounds that inhibit a noncovalent E2 enzyme-ubiquitin complex.
Article in Science advances, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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The trial behind it
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Who cites it
19 citing papers in PubMed.
- Ubiquitin family as novel protein partners for molecular glues.npj drug discovery · 2026Review
- The role of ubiquitin system in ageing-related diseases and potential therapeutic opportunities.Molecular biomedicine · 2026Review
- TPDdb: the comprehensive database of targeted protein degrader.Nucleic acids research · 2026Article
- Activation of parkin by a molecular glue.Nature communications · 2024Article
- Targeted protein degradation using chimeric human E2 ubiquitin-conjugating enzymes.Communications biology · 2024Article
- A Novel Confocal Scanning Protein-Protein Interaction Assay (PPI-CONA) Reveals Exceptional Selectivity and Specificity of CC0651, a Small Molecule Binding Enhancer of the Weak Interaction between the E2 Ubiquitin-Conjugating Enzyme CDC34A and Ubiquitin.Bioconjugate chemistry · 2024Article
- Article
- A transient vesicular glue for amplification and temporal regulation of biocatalytic reaction networks.Chemical science · 2023Article
- Molecular Glue Discovery: Current and Future Approaches.Journal of medicinal chemistry · 2023Review
- Proximity-Based Modalities for Biology and Medicine.ACS central science · 2023Review
- Novel approaches to targeted protein degradation technologies in drug discovery.Expert opinion on drug discovery · 2023Review
- A screen for MeCP2-TBL1 interaction inhibitors using a luminescence-based assay.Scientific reports · 2023Article
- Protein-protein interfaces in molecular glue-induced ternary complexes: classification, characterization, and prediction.RSC chemical biology · 2023Review
- From seeds to trees: how E2 enzymes grow ubiquitin chains.Biochemical Society transactions · 2023Review
- Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence.Journal of the American Chemical Society · 2023Review
- Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic.Biochemistry · 2023Review
- Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs.Journal of molecular biology · 2022Review
- Article
- Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein-Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
14 authors.
Funding
Abstract
Pharmacological control of the ubiquitin-proteasome system (UPS) is of intense interest in drug discovery. Here, we report the development of chemical inhibitors of the ubiquitin-conjugating (E2) enzyme CDC34A (also known as UBE2R1), which donates activated ubiquitin to the cullin-RING ligase (CRL) family of ubiquitin ligase (E3) enzymes. A FRET-based interaction assay was used to screen for novel compounds that stabilize the noncovalent complex between CDC34A and ubiquitin, and thereby inhibit the CDC34A catalytic cycle. An isonipecotamide hit compound was elaborated into analogs with ~1000-fold increased potency in stabilizing the CDC34A-ubiquitin complex. These analogs specifically inhibited CDC34A-dependent ubiquitination in vitro and stabilized an E2~ubiquitin thioester reaction intermediate in cells. The x-ray crystal structure of a CDC34A-ubiquitin-inhibitor complex uncovered the basis for analog structure-activity relationships. The development of chemical stabilizers of the CDC34A-ubiquitin complex illustrates a general strategy for de novo discovery of molecular glue compounds that stabilize weak protein interactions.
Identifiers
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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.