Targeted Protein Degradation (TPD) is no longer an emerging field, it’s a core strategy in modern drug discovery. And as the science advances, so does the language.
If you’re working on degraders in 2025, simply knowing what a PROTAC is isn’t enough. From AI-guided design to subcellular PK profiling, researchers are rethinking how they define, measure, and optimize every step of the degradation process.
Here are 10 essential and evolved terms to keep you ahead of the curve.
1. Ternary Complex
What it is:
The three-part complex formed by the degrader, target protein, and E3 ligase.
What’s new:
Success is no longer about forming the complex, it’s about how long it lasts (residence time), how it forms (cooperativity), and how productive it is. Techniques like SPR-MS and TR-FRET help track these real-time dynamics.
2. Hook Effect
What it is:
At high degrader concentrations, degradation efficiency drops due to unproductive binary binding.
What’s new:
In 2025, it’s modeled and managed. Advanced simulations help guide linker design and dosing strategies that minimize the effect while maintaining potency.
3. Molecular Glue
What it is:
Small molecules that stabilize protein–protein interactions without a linker.
What’s new:
Modern glues target cryptic or allosteric pockets and are discovered using fragment-based and AI-enhanced screening. Several new glues are in clinical pipelines targeting Cyclin K, BCL6, and more.
4. LYTAC, AUTAC & ATTEC
What they are:
Degrader classes that direct proteins to the lysosome (LYTAC) or autophagosome (AUTAC, ATTEC).
What’s new:
- LYTACs now use antibody or glycoprotein motifs to guide surface proteins into lysosomes.
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AUTACs/ATTECs apply “eat me” tags recognized by selective autophagy.
These approaches expand TPD’s reach beyond the intracellular proteasome.
5. E3 Ligase Repertoire
What it is:
The catalog of enzymes used to tag proteins with ubiquitin.
What’s new:
Researchers now select E3s based on tissue expression or disease specificity e.g., DCAF16 for CNS targets, RNF114 for epithelial cancers. Ligase-switchable designs are emerging to control degradation in precise contexts.
6. Pharmacokinetics (PK), Pharmacodynamics (PD) & Intracellular Exposure
What it is:
The movement and effect of degraders inside the body and cells.
What’s new:
Subcellular PK/PD is now measurable. Imaging mass spec tracks where degraders go (cytosol? nucleus? lysosome?) and how long they engage their targets. This informs more efficient drug delivery and activity.
7. RIPTACs & TriTACs
What they are:
Next-gen PROTACs that require additional biological conditions to activate.
What’s new:
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RIPTACs only degrade proteins in cells expressing a second “docking” receptor—offering disease-specific targeting.
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TriTACs add a third arm to improve selectivity and control.
These tools bring conditional degradation one step closer to clinical safety.
8. AI-Guided Design
What it is:
Machine learning models that help predict PROTAC structures and activities.
What’s new:
In 2025, models like DeepTernary, ET-PROTAC, and DegradeMaster simulate ternary complex formation, optimize linkers, and rank degrader candidates—often saving months in development time.
9. Target Engagement & Proteomic Profiling
What it is:
Measuring whether a degrader binds to and destroys its intended target.
What’s new:
Today, scientists use clickable PROTACs, TMT-based MS, and bioorthogonal probes to capture proteome-wide engagement. Real-time assays distinguish between transient binding and actual degradation.
10. Biomarkers & Combination Strategies
What they are:
Tools to track degrader effectiveness—and methods to improve it.
What’s new:
TPD is now part of combination regimens. Clinical trials are pairing PROTACs with immunotherapies, ADCs, and PI3K inhibitors. Biomarkers like E3 expression or ubiquitination signatures help identify responders and avoid resistance.
Ready for What’s Next in TPD?
In 2025, successful TPD programs are built on precision: molecular, spatial, and strategic.
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Use AI tools to streamline structure and linker design
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Track ternary kinetics, not just formation
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Choose context-specific E3 ligases to reduce off-target risks
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Quantify degradation proteome-wide early in the workflow
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Consider hybrid and conditionally activated degraders for the next generation
