ArticleJournal of pharmacokinetics and pharmacodynamics2021
A kinetic proofreading model for bispecific protein degraders.
Article in Journal of pharmacokinetics and pharmacodynamics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 39 citations in OpenAlex.
- Advancing PROTAC therapeutics through chemistry-guided design of smart delivery systems.Acta pharmacologica Sinica · 2026Review
- A mechanistic pharmacokinetic-pharmacodynamic model for degrader-antibody conjugates.Journal of pharmacokinetics and pharmacodynamics · 2026Article
- Exploiting Pharmacokinetic/Pharmacodynamic Methods for Optimizing and Accelerating Drug Development of Innovative Anti-Infectives.ChemMedChem · 2026Review
- A Kinetic Scout Approach Accelerates Targeted Protein Degrader Development.Angewandte Chemie (International ed. in English) · 2025Article
- A Kinetic Scout Approach Accelerates Targeted Protein Degrader Development.bioRxiv : the preprint server for biology · 2024Article
- Kinetic Proofreading Can Enhance Specificity in a Nonenzymatic DNA Strand Displacement Network.Journal of the American Chemical Society · 2024Article
- 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
- Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods.Journal of chemical information and modeling · 2023Review
- Delivering on the promise of protein degraders.Nature reviews. Drug discovery · 2023Review
- Protein degraders enter the clinic - a new approach to cancer therapy.Nature reviews. Clinical oncology · 2023Review
- Modeling the Effect of Cooperativity in Ternary Complex Formation and Targeted Protein Degradation Mediated by Heterobifunctional Degraders.ACS bio & med chem Au · 2023Article
- A Mechanistic Pharmacodynamic Modeling Framework for the Assessment and Optimization of Proteolysis Targeting Chimeras (PROTACs).Pharmaceutics · 2023Article
- Algorithmic multiscale analysis for the FcRn mediated regulation of antibody PK in human.Scientific reports · 2022Article
- Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms.ACS central science · 2021Review
- Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation.RSC chemical biology · 2021Review
- Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs.The Journal of biological chemistryReview
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Bispecific protein degraders (BPDs) engage the ubiquitin-proteasome system (UPS) to catalytically degrade intracellular proteins through the formation of ternary complexes with the target protein and E3 ubiquitin ligases. Here, we describe the development of a mechanistic modeling framework for BPDs that includes the reaction network governing ternary complex formation and degradation via the UPS. A critical element of the model framework is a multi-step process that results in a time delay between ternary complex formation and protein degradation, thereby balancing ternary complex stability against UPS degradation rates akin to the kinetic proofreading concept that has been proposed to explain the accuracy and specificity of biological processes including protein translation and T cell receptor signal transduction. Kinetic proofreading likely plays a central role in the cell's ability to regulate substrate recognition and degradation by the UPS, and the model presented here applies this concept in the context of a quantitative pharmacokinetic (PK)-pharmacodynamic (PD) framework to inform the design of potent and selective BPDs.
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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.