ArticleEuropean journal of medicinal chemistry2021
Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries.
Article in European journal of medicinal chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 62 citations in OpenAlex.
- Targeting p53 pathways: mechanisms, structures, and advances in therapy.Signal transduction and targeted therapy · 2023Pooled it
- Dispiroindolinone-Glutarimide Conjugates: Synthesis and Evaluation as Potential Hetero-PROTACs for p53 Reactivation.Molecules (Basel, Switzerland) · 2026Article
- GlueFinder: A Data-Driven Framework for the Rational Discovery of Molecular Glues.Journal of chemical information and modeling · 2026Article
- Exploring Novel E3 Ligases and Neosubstrates for Molecular Glue Degraders and Therapeutic Applications in Cancer.Oncology research · 2026Review
- Cancer Biology of GSPT1: Mechanisms and Targeted Therapy Opportunities of Molecular Glue Degraders.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- GlueFinder: A Data-Driven Framework for the Rational Discovery of Molecular Glues.bioRxiv : the preprint server for biology · 2025Article
- Review
- Dual functionality of MDM2 in PROTACs expands the horizons of targeted protein degradation.Biomarker research · 2025Review
- Synthesis, biological evaluation and clinical trials of Cereblon-based PROTACs.Communications chemistry · 2025Review
- Discovery of Drugs Targeting Mutant p53 and Progress in Nano-Enabled Therapeutic Strategy for p53-Mutated Cancers.Biomolecules · 2025Review
- Dual inhibitor of MDM2 and NFAT1 for experimental therapy of breast cancer:Frontiers in pharmacology · 2025Article
- Targeting MDM2, RAS, and PCNA for cancer targeted therapy: pan-cancer approaches vs. cancer-specific strategies.Frontiers in pharmacology · 2025Review
- p53: The Multifaceted Roles of Covalent Modifications in Cancer.Pharmaceuticals (Basel, Switzerland) · 2024Review
- MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future.Pharmacological reviews · 2024Review
- Anhydrous and Stereoretentive Fluoride-Enhanced Suzuki-Miyaura Coupling of Immunomodulatory Imide Drug Derivatives.The Journal of organic chemistry · 2024Article
- Targeting reversible post-translational modifications with PROTACs: a focus on enzymes modifying protein lysine and arginine residues.Journal of enzyme inhibition and medicinal chemistry · 2023Review
- A platform for the rapid synthesis of molecular glues (Rapid-Glue) under miniaturized conditions for direct biological screening.European journal of medicinal chemistry · 2023Article
- Recent advances in targeting the "undruggable" proteins: from drug discovery to clinical trials.Signal transduction and targeted therapy · 2023Review
- Review
- Structural rationalization of GSPT1 and IKZF1 degradation by thalidomide molecular glue derivatives.RSC medicinal chemistry · 2023Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Proteolysis targeting chimeras (PROTACs) have gained tremendous interest in both the academic and pharmaceutical communities. This opens a new way to regulate the cellular protein homeostasis, especially for disease-related proteins. In this work, we designed and synthesized a series of MDM2 degraders based on ligands that were readily prepared by a four-component Ugi reaction. After extensive optimization based on anti-proliferation and MDM2 degradation, WB214 was identified as the most potent anti-proliferative agent in various leukemia cell lines. Surprisingly, our mechanistic investigations indicated that WB214 not only effectively induced the degradation of MDM2, but also led to the degradation of p53. Further studies revealed that WB214 degraded MDM2 as a molecular glue. WB214 and its related analogues did not bind to MDM2 in the p53 binding region and MDM2 was discovered as a novel neo-substrate of the E3 ligase cereblon. Finally, we found that WB214 could potently degrade GSPT1, which could rationalize the inhibition of cell growth. A selective degrader for GSPT1 over MDM2 was then developed through systematically varying different motifs.
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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.