ArticleThe Journal of biological chemistry2020
A suite of mathematical solutions to describe ternary complex formation and their application to targeted protein degradation by heterobifunctional ligands.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 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
- PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Phosphoinositides and inositol phosphates as molecular glues.FEBS letters · 2026Review
- A real-time FRET ubiquitin transfer assay for quantitative characterization of ternary complexes in targeted protein degradation.Cell reports methods · 2026Article
- TogoPhosTAC as a delivery-ready platform for targeted protein dephosphorylation.Nature communications · 2026Article
- A quantitative approach for defining the degradability landscape of protein degraders.Nature communications · 2026Article
- Unhooking the Hook: Optimization of the Aurora A Targeting PROTACJournal of medicinal chemistry · 2026Article
- Exploiting Pharmacokinetic/Pharmacodynamic Methods for Optimizing and Accelerating Drug Development of Innovative Anti-Infectives.ChemMedChem · 2026Review
- Mechanistic insights into PROTAC-mediated degradation through an integrated framework of molecular dynamics, free energy landscapes, and quantum mechanics: A case study on kinase degraders.Journal of computer-aided molecular design · 2025Article
- Article
- 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
- Article
- DegraderTCM: A Computationally Sparing Approach for Predicting Ternary Degradation Complexes.ACS medicinal chemistry letters · 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
- Development and Applications of Chimera Platforms for Tyrosine Phosphorylation.ACS central science · 2023Article
- Proximity-Based Modalities for Biology and Medicine.ACS central science · 2023Review
- iTAG an optimized IMiD-induced degron for targeted protein degradation in human and murine cells.iScience · 2023Article
- A model-informed method to retrieve intrinsic from apparent cooperativity and project cellular target occupancy for ternary complex-forming compounds.RSC chemical biology · 2023Article
- Straightforward model construction and analysis of multicomponent biomolecular systems in equilibrium.RSC chemical biology · 2023Article
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Abstract
Small molecule-induced targeted protein degradation by heterobifunctional ligands or molecular glues represents a new modality in drug development, allowing development of therapeutic agents for targets previously considered undruggable. Successful target engagement requires the formation of a ternary complex (TC) when the ligand brings its target protein in contact with an E3 ubiquitin ligase. Unlike traditional drugs, where target engagement can be described by a simple bimolecular equilibrium equation, similar mathematical tools are currently not available to describe TC formation in a universal manner. This current limitation substantially increases the challenges of developing drugs with targeted protein degradation mechanism. In this article, I provide a full, exact, and universal mathematical description of the TC system at equilibrium for the first time. I have also constructed a comprehensive suite of mathematical tools for quantitative measurement of target engagement and equilibrium constants from experimental data. Mechanistic explanations are provided for many common challenges associated with developing this type of therapeutic agent. Insights from these analyses provide testable hypotheses and grant direction to drug development efforts in this promising area. The mathematical and analytical tools described in this article may also have broader applications in other areas of biology and chemistry in which ternary complexes are observed.
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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.