In late 2023, the biotech world lit up with exciting news from clinical trials across the U.S. Several companies revealed early data. It showed that their new drug candidates could remove disease-causing proteins entirely. This contrasts with just blocking them. This breakthrough approach, called targeted protein degradation, taps into the cell’s own “trash disposal” system to destroy harmful proteins. It’s a bold shift. It’s opening new doors for the $800 billion pharmaceutical industry. This approach reaches areas traditional drugs could never access.
Targeted protein degradation is revolutionary due to its ability to address the so-called “undruggable” proteins. These are proteins without proper binding sites for typical inhibitors. Thanks to powerful technologies like PROTACs and molecular glues, this next-generation strategy is reshaping how scientists discover and design medicines.
What You’ll Learn in This Guide:
- What targeted protein degradation is and why it’s superior to traditional inhibitors
- How PROTACs and molecular glues work at the molecular level (step-by-step breakdown)
- AI-powered design tools that are accelerating PROTAC discovery
- Current US clinical trials and which companies are leading the charge
- Real challenges researchers face and how they’re solving them
Ready to explore the future of medicine? Let’s dive in.
What Is Targeted Protein Degradation?
Imagine your cell as a well-organized city. When a protein starts misbehaving or causes disease, traditional drugs act like traffic cops. They block the bad protein for a while but don’t remove it completely. Targeted Protein Degradation works quite differently. It acts like a precise cleanup crew. It sends the faulty protein straight to the city’s recycling center. There, it’s broken down and destroyed for good.
How the Cell’s Recycling System Works: The Core Mechanism Explained
The process relies on a natural cellular mechanism called the ubiquitin-proteasome system.
- Ubiquitin: This is a small protein tag. Think of it as a “trash ticket” or a red flag.
- E3 Ligase: This enzyme is the cell’s “tagging station.” Its job is to attach ubiquitin tags to proteins that are ready for disposal.
- Proteasome: This is the cell’s actual “recycling bin.” It is a large, barrel-shaped complex. It recognizes and chews up any protein tagged with enough ubiquitin.
TPD drugs, like PROTACs or molecular glue degraders, don’t perform the degradation themselves. They hijack the E3 ligase so it tags the protein you want to destroy. It’s a classic case of cellular espionage.
Core Components of a Degrader Molecule
A PROTAC (Proteolysis Targeting Chimera) molecule is made up of three essential parts, acting as a molecular bridge:
- Warhead (Target Ligand): This end binds specifically to the target protein you want to degrade.
- E3 Ligase Ligand: This end binds to the E3 ligase enzyme, recruiting the cell’s disposal mechanism.
- Linker Region: This chemical chain connects the warhead and the E3 ligase ligand. It holds them at the perfect distance to initiate the degradation process.
PROTACs vs Molecular Glues vs Traditional Inhibitors
Not all protein degraders are created equal. Let’s break down the three main approaches and when each shines.
| Feature | Traditional Inhibitors | PROTACs | Molecular Glues |
|---|---|---|---|
| Mechanism | Blocks a protein’s active site (like a plug in a socket). | Acts as a bifunctional bridge to tag a protein for destruction. | Induces a new interaction between the E3 ligase and the target protein. |
| Result | Temporary inactivation of the protein’s function. | Complete, catalytic degradation of the target protein. | Complete, catalytic degradation of the target protein. |
| Dose Requirement | Requires high concentration (stoichiometric) to saturate and block the protein. | Requires low concentration (sub-stoichiometric) as the molecule is recycled after use. | Requires low concentration, acts by stabilizing a new interface. |
| Molecule Size | Small (typically <500 Da). | Larger, typically $800-1200$ Da. | Small (typically <500 Da). |
When to Choose Which Degrader
- You’d prefer a PROTAC when: The target protein has a known binding site. A good warhead exists. However, you need to achieve total protein knockdown, not just temporary inhibition. Their size is a challenge for permeability, but their flexibility allows them to target diverse proteins.
- Molecular Glues work better when: You need a smaller molecule, which is better for oral dosing. You can tolerate a bit less control over the specific protein interface. This approach hopes to discover a natural-like interaction that forces the target and the E3 ligase together. Molecular glues are harder to discover, but offer superior degrader pharmacokinetics.
How Does a PROTAC Work? Step-by-Step Walkthrough
Let’s track a PROTAC molecule on its journey inside a living cell. When we see how it works step by step, we gain a better understanding. This helps us see why targeted protein degradation is such a groundbreaking new approach.
1: Target Binding by Warhead
Once the PROTAC molecule enters the cell, it starts looking for its target protein. The warhead part quickly recognizes and attaches to a specific spot on the disease-causing protein. This process isn’t random, the warhead is carefully designed using known inhibitors or ligands that already bind to that protein. The strength of this binding is crucial. If it’s too weak, the PROTAC drifts away. If it’s too strong, it may not detach even after the protein is broken down.
2: Recruitment of E3 Ligase
The other end of the PROTAC molecule remains attached to the target protein. It recruits an E3 ligase. This ligase is one of the cell’s ~600+ protein disposal tags.
Most PROTACs use well-characterized E3 ligases like:
- VHL (Von Hippel-Lindau): The workhorse of PROTAC design
- Cereblon (CRBN): Made famous by IMiD drugs
- IAP (Inhibitor of Apoptosis Proteins): Emerging player in the field
Each E3 ligase has tissue-specific expression and distinct target preferences, which scientists exploit for selectivity.
3: Ternary Complex Formation
This is the real magic. The PROTAC pulls the target protein and the E3 ligase close together. This action creates a stable three-part complex. Such a complex doesn’t normally form on its own. The shape and stability of this complex matter a lot. Scientists use computer modeling. They also use advanced tools like cryo-EM. These tools help predict if the linker’s length will align the proteins correctly.
4: Ubiquitination of Target
Once the complex forms, the E3 ligase takes action. It attaches tiny ubiquitin molecules, each made of 76 amino acids, to specific lysine sites on the target protein. Typically, at least four ubiquitin molecules link together to form a chain, known as polyubiquitination. This chain works like a cellular tag that clearly signals, “It’s time to destroy this protein.”
5: Proteasomal Degradation
The 26S proteasome, a barrel-shaped molecular machine that works like the cell’s paper shredder, recognizes the protein tagged with ubiquitin. It then unfolds the target protein and pulls it into its core. There, the protein is cut into tiny peptides and amino acids. It is completely destroyed.
At the same time, the PROTAC molecule stays unharmed and moves on to hunt for another target. Due to this catalytic process, a single PROTAC can break down many copies of the same protein. This makes it a highly efficient system.
6: Result & Functional Read-Out in Cell
The cell now has fewer (or zero) copies of the disease-causing protein. Unlike inhibition, where the protein sits around inactive, degradation creates actual absence.
Researchers measure success using:
- Western blots: Showing decreased protein levels
- Mass spectrometry: Quantifying proteome-wide changes
- Functional assays: Demonstrating phenotypic effects (like cancer cell death)
The entire cycle from PROTAC binding to complete degradation can take 2-8 hours. Maximal degradation often occurs 4-24 hours after treatment.
PROTAC Design: How Scientists Create Targeted Protein Degraders
Creating an effective degrader is one of the toughest tasks in synthetic chemistry and biological engineering. The process is complex and requires carefully adjusting how the molecule’s structure influences its activity.
Target Selection Criteria
Not all proteins are equally easy to degrade. Scientists look for proteins that:
- Are clearly disease-driving (e.g., specific transcription factors in cancer).
- Exhibit rapid turnover (the natural rate at which the protein is replaced).
- Have regions that are accessible for the E3 ligase to attach the ubiquitin tag.
Choosing a Warhead and E3 Ligase
- Warhead: Often, drug discovery starts by repurposing an existing inhibitor scaffold. This scaffold is a molecule already known to bind the target protein. If one doesn’t exist, a new ligand warhead must be discovered.
- E3 Ligase Options: The most commonly recruited E3 ligases are Cereblon (CRBN) and Von Hippel–Lindau (VHL). However, research is actively exploring new E3 ligase degraders to expand the range of targets and potentially improve selectivity.
Linker Length and Chemistry Considerations
The linker region plays a key role in PROTAC design and is also the trickiest part to get right. Its length and flexibility decide how the ternary complex takes shape. If the linker is too short or too long, the E3 ligase won’t align properly for ubiquitination. Scientists usually fine-tune the linker length through detailed structure–activity relationship (SAR) studies to achieve the perfect balance.
In-vitro and In-vivo Validation
After synthesis, candidate molecules go through rigorous testing:
- Cell-based assays: Testing in living cells to confirm the molecule causes degradation, not just inhibition.
- Selectivity: Ensuring no off-target degradation of similar, healthy proteins occurs.
- ADME/Toxicity: Assessing the molecule’s Absorption, Distribution, Metabolism, and Excretion (degrader pharmacokinetics). Evaluating its overall toxicity in vivo (in animal models) to determine safety.
AI and Computational Design: Latest Advances and Applications
Here’s where things get really exciting. Artificial intelligence is dramatically accelerating PROTAC design, turning what used to take years into months.
What AI-Powered PROTAC Design Looks Like Today
Traditional PROTAC development was trial-and-error. Scientists would synthesize 50-100 molecules with different linkers and warheads, hoping one worked.
AI changes the game. Machine learning models can now:
- Predict ternary complex formation and stability
- Optimize linker chemistry for desired properties
- Forecast degradation efficiency before synthesis
- Screen virtual libraries of millions of compounds
The result? Higher success rates and fewer wasted resources.
Generative Models & Ternary Complex Prediction
Generative models like those based on diffusion or transformer architectures can design novel PROTAC structures from scratch. They learn patterns from existing degraders and propose new candidates likely to form productive ternary complexes.
AlphaFold and similar protein structure prediction tools help visualize protein interactions. They show how target proteins, E3 ligases, and PROTACs will interact—even before experimental structures exist.
Molecular dynamics simulations powered by AI can simulate millions of conformational states. These simulations identify optimal linker lengths. They also determine chemistries that stabilize the ternary complex.
Companies and academic labs are building specialized tools:
- PROTAC-DB: Database of known PROTACs with activity data
- PRosettaC: Computational platform for PROTAC design
- DeepPROTACs: Neural networks trained on degradation data
How AI Shortens Discovery Time & Improves Selectivity
The traditional medicinal chemistry cycle for PROTACs took 18-36 months from target selection to lead candidate.
AI-driven approaches are cutting that to 6-12 months.
AI also helps predict and prevent off-target degradation. By modeling how a PROTAC might interact with the cell’s entire proteome, researchers can flag potential problems before synthesis.
AI-Designed PROTAC Success
In 2024, researchers at MIT used a generative AI model to design a cereblon-based PROTAC. This PROTAC targets a transcription factor previously considered undruggable. The AI-proposed molecule showed 85% target degradation with minimal off-targets, a result that would have required years of traditional optimization.
The model analyzed over 100,000 possible linker-warhead combinations in silico, prioritizing candidates based on predicted ternary complex stability scores. Only five molecules needed actual synthesis to find the winner.
This represents a paradigm shift: from human intuition-guided trial-and-error to AI-accelerated rational design.
Targeted Protein Degradation in the U.S.: Clinical Progress and Industry Landscape
The United States is leading the global race in bringing targeted protein degradation to patients. Let’s look at who’s doing what and where the field stands today.
Leading US Companies in the PROTAC Space
Arvinas (New Haven, CT) is the undisputed pioneer. PROTAC inventor Craig Crews founded the company. They are advancing multiple degraders through clinical trials. This includes ARV-471 (estrogen receptor degrader) and ARV-110 (androgen receptor degrader).
Nurix Therapeutics (San Francisco, CA) focuses on E3 ligase modulators. The company has several PROTAC candidates in development. These candidates particularly target BTK and other kinases.
Kymera Therapeutics (Watertown, MA) specializes in degraders for immunology and oncology. Their lead candidate targets IRAK4, a key protein in inflammatory signaling.
C4 Therapeutics (Watertown, MA) emerged from Dana-Farber Cancer Institute with a platform focused on small molecule degraders, including molecular glues.
Plexium (San Diego, CA) is developing next-generation degraders with improved pharmacokinetic properties.
Current US-Based Clinical Trials
As of October 2025, several PROTACs are in human testing:
ARV-471 (Arvinas) – Phase 3 trial (NCT05654623) for estrogen receptor-positive breast cancer. This is the most advanced PROTAC globally.
ARV-110 (Arvinas) – Phase 2 trial (NCT03888612) for metastatic castration-resistant prostate cancer targeting the androgen receptor.
NX-2127 (Nurix) – Phase 1 trial (NCT04830137) for B-cell malignancies, using BTK degradation.
KT-474 (Kymera) – Phase 1 trial (NCT04772885) for atopic dermatitis and hidradenitis suppurativa, targeting IRAK4.
CFT7455 (C4 Therapeutics) – Phase 1/2 trial (NCT04756726) for multiple myeloma and non-Hodgkin lymphoma.
You can search these trials and find updates at ClinicalTrials.gov.
Regulatory & FDA Status
The FDA has shown strong interest in targeted protein degradation. In 2022, they granted Fast Track designation to ARV-471, signaling confidence in the approach.
Key regulatory considerations:
- Novel mechanism requires extensive mechanistic studies
- Need to demonstrate advantages over existing therapies
- Safety monitoring for immune-related events
- Understanding tissue-specific effects
No PROTAC has achieved FDA approval yet, but ARV-471’s Phase 3 advancement suggests approval could come as early as 2026-2027.
Recent Investor & Startup Activity
The sector is red-hot with investment. In 2024 alone:
- Arvinas secured $200M in financing to advance late-stage programs
- Multiple biotech startups raised Series A/B rounds exceeding $50M
- Big Pharma partnerships accelerated: Pfizer, Novartis, and Roche all announced PROTAC collaborations
This influx of capital is funding next-generation platforms, AI integration, and exploration of novel E3 ligases beyond VHL and cereblon.
ARV-471 Case Study: A Breakthrough Example of Targeted Protein Degradation
Let’s examine the most advanced PROTAC in clinical development to understand the real-world path from bench to beside.
The Science Behind ARV-471
ARV-471 is a PROTAC designed to degrade the estrogen receptor (ER) in breast cancer cells. Approximately 70% of breast cancers are ER-positive, meaning they depend on estrogen signaling to grow. Traditional drugs like tamoxifen and fulvestrant block ER function. ARV-471 eliminates the receptor entirely.
Design details:
- Warhead: Derived from known ER antagonist structures
- E3 ligase: Uses VHL ligand
- Linker: Optimized through extensive SAR studies
The molecule was selected from over 100 candidates based on degradation potency, selectivity, and oral bioavailability.
Preclinical Development Phase
In laboratory studies, ARV-471 demonstrated:
- 90% ER degradation in ER-positive breast cancer cell lines
- Superior anti-tumor activity compared to fulvestrant in mouse models
- Good oral availability (rare for PROTACs)
- Minimal off-target protein degradation
These results, published in peer-reviewed journals, provided the foundation for FDA approval to begin human trials.
Clinical Trial Progression
Phase 1 (2019-2021): Dose-escalation study in patients with advanced ER+/HER2- breast cancer who had exhausted other options. Results showed the drug was tolerable, achieved target engagement (ER degradation confirmed in tumor biopsies), and produced preliminary efficacy signals.
Phase 2 (2021-2023): Expanded testing in combination with other agents. Clinical benefit rate of ~40% in heavily pre-treated patients, competitive with existing options.
Phase 3 (2023-present): Trial NCT05654623 comparing ARV-471 to fulvestrant in patients with ER+/HER2- locally advanced or metastatic breast cancer. Enrollment completed with ~400 patients. Primary endpoint is progression-free survival.
Current Status & What’s Next
As of October 2025, Phase 3 data is expected in late 2025 or early 2026. If positive, Arvinas will submit a New Drug Application (NDA) to the FDA. Approval would be historic. It would be the first purpose-designed PROTAC to reach the market. This does not include the serendipitously discovered molecular glue degraders already approved. ARV-471 represents validation that targeted protein degradation can deliver real clinical benefits, not just elegant biochemistry.
Conclusion
Targeted protein degradation isn’t just a small upgrade in drug treatment, it’s a complete game-changer. Instead of simply blocking harmful proteins for a short time, this approach removes them permanently. Scientists use PROTACs and molecular glues to destroy disease-causing proteins completely. This opens the door to treatments for conditions once thought impossible to cure.
Modern chemistry is teaming up with AI-powered PROTAC design. Researchers are creating powerful new ways to fight tough diseases like aggressive cancers and neurodegenerative disorders. The result? A wave of fresh, effective therapies that could change how we think about medicine.
The ubiquitin-proteasome system, once seen as a routine cellular process, has now become the star of drug discovery. It’s an exciting moment, watching the future of medicine take shape right in front of us.
Test your knowledge by taking our Biochemistry Test.
Recommended Resources for Curious Minds
If you’re excited to explore more about how targeted protein degradation works, check out these top resources. They’re a great next step to deepen your understanding of where it’s being applied.
- The 2023-2028 World Outlook for Small Molecule Drug Discovery by Prof Philip M. Parker Ph.D.
- Protein Degradation in Health and Disease by Michele Reboud-Ravaux
- Artificial Intelligence in Drug Design by Alexander Heifetz
Frequently Asked Questions about Targeted Protein Degradation
No, not yet. A protein must have a surface to which the ligand warhead can bind and, critically, a surface that the E3 ligase can access to attach the ubiquitin tag when the ternary complex forms. Proteins that lack this accessible surface are still considered challenging to target.
Safety comes first in PROTAC development. These molecules are carefully designed to target only specific proteins, reducing the risk of unwanted degradation. Early human clinical trials (identified by their NCT numbers) have shown that PROTACs generally have manageable safety profiles. Still, because PROTACs are larger than traditional small molecules, they behave differently inside the body. This difference in how the body processes the drug, known as pharmacokinetics, means researchers must monitor patients closely throughout treatment.
AI doesn’t replace chemists, it empowers them to move faster. With advanced computing power, AI can quickly test and refine the linker length and geometry needed to perfect the ternary complex in PROTACs. As a result, researchers face fewer wrong turns and work with higher-quality lead molecules right from the start, cutting down the time it takes to make discoveries in the lab.
References & Further Reading
- Crews, C.M. & Deshaies, R.J. (2022). “Proteolysis-Targeting Chimeras (PROTACs) Come of Age.” Nature Reviews Drug Discovery, 21(11), 783-784.
- Békés, M., Langley, D.R., & Crews, C.M. (2022). “PROTAC Targeted Protein Degraders: The Past Is Prologue.” Nature Reviews Drug Discovery, 21(3), 181-200.
- Schapira, M., Calabrese, M.F., Bullock, A.N., & Crews, C.M. (2019). “Targeted Protein Degradation: Expanding the Toolbox.” Nature Reviews Drug Discovery, 18(12), 949-963.
- Pettersson, M. & Crews, C.M. (2019). “PROteolysis TArgeting Chimeras (PROTACs) – Past, Present and Future.” Drug Discovery Today: Technologies, 31, 15-27.
- Lai, A.C. & Crews, C.M. (2017). “Induced Protein Degradation: An Emerging Drug Discovery Paradigm.” Nature Reviews Drug Discovery, 16(2), 101-114.
