ArticleJournal of medicinal chemistry2018
Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds.
Article in Journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
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Who cites it
100 citing papers in PubMed.
- Context matters in PROTAC design: navigating the trade-off between degradation and developability.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Structural basis for selective and potent degradation of IRAK4 by KT-474.Nature communications · 2026Article
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Combinatorial use of VHL and KEAP1 PROTACs reveals unexpected synergy and hook effect relief.Genes & development · 2026Article
- Lessons learned in linking PROTACs from discovery to the clinic.Nature reviews. Chemistry · 2026Review
- Conformational Dynamics in the Cell Membrane Interactions of Bispecific Targeted Degrader Therapeutics.Journal of medicinal chemistry · 2025Article
- Interpretable PROTAC Degradation Prediction With Structure-Informed Deep Ternary Attention Framework.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Proteome-Wide Discovery of Degradable Proteins Using Bifunctional Molecules.ACS central science · 2025Article
- A Chemically Induced CRISPR/dCas13Journal of medicinal chemistry · 2025Article
- Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.Journal of molecular biology · 2025Review
- Construction of PROTAC-Mediated Ternary Complex Structure Distribution Profiles Using Extensive Conformational Search.Journal of chemical information and modeling · 2025Article
- Methods to accelerate PROTAC drug discovery.The Biochemical journal · 2025Review
- Recommended Tool Compounds: Thienotriazolodiazepines-Derivatized Chemical Probes to Target BET Bromodomains.ACS pharmacology & translational science · 2025Review
- Minimizing DNA trapping while maintaining activity inhibition via selective PARP1 degrader.Cell death & disease · 2024Article
- PROTAC-mediated activation, rather than degradation, of a nuclear receptor reveals complex ligand-receptor interaction network.Structure (London, England : 1993) · 2024Article
- Non-Markovian Dynamic Models Identify Non-Canonical KRAS-VHL Encounter Complex Conformations for Novel PROTAC Design.JACS Au · 2024Article
- Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2.Nature communications · 2024Article
- An updated patent review of BRD4 degraders.Expert opinion on therapeutic patents · 2024Review
- PROteolysis-Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives.MedComm · 2024Review
- Development of Biocompatible Cu(I)-Microdevices for Bioorthogonal Uncaging and Click Reactions.Chemistry (Weinheim an der Bergstrasse, Germany) · 2024Article
40 more citing papers are in PubMed but not listed here.
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4 authors.
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Abstract
The design of proteolysis-targeting chimeras (PROTACs) is a powerful small-molecule approach for inducing protein degradation. PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Here we examined the impact of derivatizing two different BET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent tetrahydroquinoline I-BET726, via distinct exit vectors, using different polyethylene glycol linkers to VHL ligand VH032. Triazolodiazepine PROTACs exhibited positive cooperativities of ternary complex formation and were more potent degraders than tetrahydroquinoline compounds, which showed negative cooperativities instead. Marked dependency on linker length was observed for BET-degrading and cMyc-driven antiproliferative activities in acute myeloid leukemia cell lines. This work exemplifies as a cautionary tale how a more potent inhibitor does not necessarily generate more potent PROTACs and underscores the key roles played by the conjugation. The provided insights and framework for structure-activity relationships of bivalent degraders are anticipated to have wide future applicability.
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