ArticleACS bio & med chem Au2023
Modeling the Effect of Cooperativity in Ternary Complex Formation and Targeted Protein Degradation Mediated by Heterobifunctional Degraders.
Article in ACS bio & med chem Au, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
- Context matters in PROTAC design: navigating the trade-off between degradation and developability.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- A Versatile DNA-Encoded Library Platform for the Discovery of Highly Cooperative Chemical Inducers of Proximity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- A quantitative approach for defining the degradability landscape of protein degraders.Nature communications · 2026Article
- Development of TSSK1 and TSSK2 Targeted Degraders Reveals Sperm Machinery for Protein Degradation and Potential for Nonhormonal Male Contraception.Journal of medicinal chemistry · 2026Article
- Biophysical Modeling Elucidates Mechanistic Principles for Rational Molecular Glue Design.Journal of chemical information and modeling · 2026Article
- Cyclin-E/A/CDK1/2 Kinetic Landscapes Drive Cell Cycle Phase-Specific Progression and Guide Cyclin-E Degradation Strategy.Journal of chemical information and modeling · 2026Article
- How multispecific molecules are transforming pharmacotherapy.Nature reviews. Drug discovery · 2025Review
- Targeted Protein Degradation for Agricultural Applications: Rationale, Challenges, and Outlook.ACS bio & med chem Au · 2025Review
- Review
- Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes.Nature communications · 2025Article
- A Complete Mechanistic Framework for Molecular Glue Characterization.Journal of the American Chemical Society · 2025Article
- Targeted degradation of extracellular proteins: state of the art and diversity of degrader designs.Journal of hematology & oncology · 2025Review
- Ternary Complex Modeling, Induced Fit Docking and Molecular Dynamics Simulations as a Successful Approach for the Design of VHL-Mediated PROTACs Targeting the Kinase FLT3.Archiv der Pharmazie · 2025Article
- A Kinetic Scout Approach Accelerates Targeted Protein Degrader Development.Angewandte Chemie (International ed. in English) · 2025Article
- Rationalize the Functional Roles of Protein-Protein Interactions in Targeted Protein Degradation by Kinetic Monte-Carlo Simulations.bioRxiv : the preprint server for biology · 2024Article
- A Kinetic Scout Approach Accelerates Targeted Protein Degrader Development.bioRxiv : the preprint server for biology · 2024Article
- Bayesian network models identify cooperative GPCR:G protein interactions that contribute to G protein coupling.The Journal of biological chemistry · 2024Article
- Bayesian network models identify co-operative GPCR:G protein interactions that contribute to G protein coupling.bioRxiv : the preprint server for biology · 2023Article
- An integrated modelling approach for targeted degradation: insights on optimization, data requirements and PKPD predictions from semi- or fully-mechanistic models and exact steady state solutions.Journal of pharmacokinetics and pharmacodynamics · 2023Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chemically induced proximity between certain endogenous enzymes and a protein of interest (POI) inside cells may cause post-translational modifications to the POI with biological consequences and potential therapeutic effects. Heterobifunctional (HBF) molecules that bind with one functional part to a target POI and with the other to an E3 ligase induce the formation of a target-HBF-E3 ternary complex, which can lead to ubiquitination and proteasomal degradation of the POI. Targeted protein degradation (TPD) by HBFs offers a promising approach to modulate disease-associated proteins, especially those that are intractable using other therapeutic approaches, such as enzymatic inhibition. The three-way interactions among the HBF, the target POI, and the ligase-including the protein-protein interaction between the POI and the ligase-contribute to the stability of the ternary complex, manifested as positive or negative binding cooperativity in its formation. How such cooperativity affects HBF-mediated degradation is an open question. In this work, we develop a pharmacodynamic model that describes the kinetics of the key reactions in the TPD process, and we use this model to investigate the role of cooperativity in the ternary complex formation and in the target POI degradation. Our model establishes the quantitative connection between the ternary complex stability and the degradation efficiency through the former's effect on the rate of catalytic turnover. We also develop a statistical inference model for determining cooperativity in intracellular ternary complex formation from cellular assay data and demonstrate it by quantifying the change in cooperativity due to site-directed mutagenesis at the POI-ligase interface of the SMARCA2-ACBI1-VHL ternary complex. Our pharmacodynamic model provides a quantitative framework to dissect the complex HBF-mediated TPD process and may inform the rational design of effective HBF degraders.
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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.