ArticleAngewandte Chemie (International ed. in English)2020
Structure-Based Design of a Macrocyclic PROTAC.
Article in Angewandte Chemie (International ed. in English), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers.
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Who cites it
107 citing papers in PubMed, 226 citations in OpenAlex.
- Evolving CRBN ligands enhance the drug-like properties of protein degraders.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Context matters in PROTAC design: navigating the trade-off between degradation and developability.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- FDA Approval of the First-Ever PROTAC: Vepdegestrant (ARV-471) Marks a New Era in Targeted Protein Degradation.Journal of medicinal chemistry · 2026Article
- Mapping Scientific Landscapes and Therapeutic Innovations of Targeted Protein Degradation: A Scientometric Review.Pharmaceutics · 2026Review
- PROTAC-mediated regulation of programmed cell death: From molecular mechanisms to therapeutic breakthroughs.Innovation (Cambridge (Mass.)) · 2026Review
- Research Trends and Emerging Frontiers in Proteolysis Targeting Chimeras (PROTACs): A Bibliometric Analysis of 2630 Publications (2001-2025).Pharmaceuticals (Basel, Switzerland) · 2026Article
- The benchmarking and application of tag-degraders in vivo to validate therapeutic targets.Nature communications · 2026Article
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Metastable Protein-Protein Interactions as a Design Principle for PROTACs: Insights from the RIPK1-VHL System.JACS Au · 2026Article
- Proteolysis-targeting chimera (PROTAC) in cancer: design principles and applications on "undruggable" targets.Biomarker research · 2026Review
- Knowledge mapping and bibliometric insights of scientific research on targeted protein degradation in oncology.Journal of cancer research and clinical oncology · 2026Review
- LinkLlama: Enabling Large Language Model for Chemically Reasonable Linker Design.bioRxiv : the preprint server for biology · 2026Article
- PROTAC-based protein degradation: a window of opportunity for melanoma therapy.Journal of biomedical science · 2026Review
- Indirect ubiquitination independent of endogenous ubiquitination machinery for targeted protein degradation.Communications chemistry · 2026Article
- Therapeutic Alternatives to Recombinant Biologics: Mechanistic Framework, Clinical Evidence, and Selection Guidance.Drug design, development and therapy · 2026Review
- Small molecules targeting the PD-1/PD-L1 axis for cancer immunotherapy.Theranostics · 2026Review
- Advantages of PROTACs in achieving selective degradation of homologous protein families.Beilstein journal of organic chemistry · 2026Review
- PRosettaC outperforms AlphaFold3 for modeling PROTAC ternary complexes.Scientific reports · 2025Article
- Review
- Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes.Nature communications · 2025Article
47 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Herein, we report the design and synthesis of a macrocyclic PROTAC by adding a cyclizing linker to the BET degrader MZ1. A co-crystal structure of macroPROTAC-1 bound in a ternary complex with VHL and the second bromodomain of Brd4 validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12-fold loss of binary binding affinity for Brd4, macroPROTAC-1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets.
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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.