ArticleJournal of medicinal chemistry2023
Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs.
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 24 papers.
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Who cites it
24 citing papers in PubMed, 42 citations in OpenAlex.
- Evolving CRBN ligands enhance the drug-like properties of protein degraders.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- The synthetic landscape of cereblon (CRBN) binders: from thalidomide to emerging chemotypes.Chemical Society reviews · 2026Review
- Optimizing CRBN-ligands for optical targeted protein degradation.RSC medicinal chemistry · 2026Article
- Fluorinated Aminopiperidones as Non-Glutarimide Thalidomide Analogs: Stereodivergent Synthesis and Validation.ChemMedChem · 2026Article
- A unified platform for the rapid assembly of glutarimides for Cereblon E3 ligase modulatory drugs.Nature communications · 2026Article
- A new 4-atom linker enables PROTAC development and imaging.RSC chemical biology · 2026Article
- Identification of a mechanism-based binding mode for a histone deacetylase 6 inhibitor.Nature communications · 2026Article
- A Facile Protocol for C(spChemMedChem · 2026Article
- Click. Screen. Degrade. A Miniaturized D2B Workflow for Rapid PROTAC Discovery.Journal of medicinal chemistry · 2026Article
- Rifamycin O as a novel CRBN ligand for targeted degradation of IKZF1/3 proteins in hematopoietic malignancies.Acta pharmaceutica Sinica. B · 2026Article
- Tuning the open-close equilibrium of Cereblon with small molecules influences protein degradation.bioRxiv : the preprint server for biology · 2025Article
- Amyloid Light Chain Proteins in Cardiovascular Disease: Pathogenesis and Emerging Therapies for Cardiac Amyloidosis.Pharmaceutical research · 2025Review
- Accurate site-specific folding via conditional diffusion based on AlphaFold3.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Mechanisms that matter: unbiased cellular screening for degraders.npj drug discovery · 2025Review
- Target Engagement Studies and Kinetic Live-Cell Degradation Assays Enable the Systematic Characterization of Histone Deacetylase 6 Degraders.ACS pharmacology & translational science · 2025Article
- Article
- Synthesis, biological evaluation and clinical trials of Cereblon-based PROTACs.Communications chemistry · 2025Review
- Accurate Site-specific Folding via Conditional Diffusion Based on Alphafold3.bioRxiv : the preprint server for biology · 2025Article
- Development and Characterization of the First Selective Class IIb Histone Deacetylase Degraders.Journal of medicinal chemistry · 2025Article
- Discovery of an LSD1 PROTAC degrader.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
Corrections and comments
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Authors and funding
21 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds.
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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.