10 Evolved Terms Every Scientist Should Know About Targeted Protein Degradation in 2025

Ready for What’s Next in TPD?

• Consider hybrid and conditionally activated degraders for the next generation

• Quantify degradation proteome-wide early in the workflow

• Choose context-specific E3 ligases to reduce off-target risks

• Track ternary kinetics, not just formation

• Use AI tools to streamline structure and linker design

In 2025, successful TPD programs are built on precision: molecular, spatial, and strategic.

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.

What they are: Tools to track degrader effectiveness—and methods to improve it.

10.  Biomarkers & Combination Strategies

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.

What it is: Measuring whether a degrader binds to and destroys its intended target.

9.  Target Engagement & Proteomic Profiling

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.

What it is: Machine learning models that help predict PROTAC structures and activities.

8. AI-Guided Design

• TriTACs add a third arm to improve selectivity and control. These tools bring conditional degradation one step closer to clinical safety.

• RIPTACs only degrade proteins in cells expressing a second “docking” receptor—offering disease-specific targeting.

What’s new:

What they are: Next-gen PROTACs that require additional biological conditions to activate.

7. RIPTACs & TriTACs

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.

What it is: The movement and effect of degraders inside the body and cells.

6. Pharmacokinetics (PK), Pharmacodynamics (PD) & Intracellular Exposure

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.

What it is: The catalog of enzymes used to tag proteins with ubiquitin.

5.  E3 Ligase Repertoire

• LYTACs now use antibody or glycoprotein motifs to guide surface proteins into lysosomes.

AUTACs/ATTECs apply “eat me” tags recognized by selective autophagy. These approaches expand TPD’s reach beyond the intracellular proteasome.

What’s new:

What they are: Degrader classes that direct proteins to the lysosome (LYTAC) or autophagosome (AUTAC, ATTEC).

4. LYTAC, AUTAC & ATTEC

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.

What it is: Small molecules that stabilize protein–protein interactions without a linker.

3. Molecular Glue

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.

What it is: At high degrader concentrations, degradation efficiency drops due to unproductive binary binding.

2. Hook Effect

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.

What it is: The three-part complex formed by the degrader, target protein, and E3 ligase.

1. Ternary Complex