Global PROTAC Clinical Progress Review: Why Is This Emerging Technology Being Called a “New Engine for Drug Discovery”?

In the field of innovative drug development, a breakthrough technology capable of reshaping the industry tends to emerge every decade or so. From monoclonal antibodies and CAR-T cell therapies to mRNA technologies, each advancement has propelled the pharmaceutical industry into a new era. In recent years, PROTAC (Proteolysis-Targeting Chimera) technology has attracted significant attention from global investors and pharmaceutical companies and is increasingly regarded as a potential driving force behind the next generation of drug discovery.

Unlike traditional drugs that work by inhibiting protein function, the core concept of PROTAC is to directly eliminate disease-causing proteins. This novel therapeutic approach not only offers solutions for many previously undruggable targets but also provides scientists with a new way to overcome long-standing bottlenecks in drug development.

From Inhibition to Degradation: A Shift in Drug Discovery Logic

For decades, most small-molecule drugs have worked by binding to the active sites of disease-related proteins and inhibiting their functions. However, many disease-associated proteins lack suitable binding pockets for conventional drugs, causing them to be classified as “undruggable targets.”

PROTAC technology offers an entirely different strategy. A PROTAC molecule typically consists of three components: a target protein ligand, an E3 ubiquitin ligase ligand, and a linker connecting the two. Once a PROTAC simultaneously binds the target protein and an E3 ligase, it triggers ubiquitination of the target protein, which is subsequently recognized and degraded by the cell’s proteasome.

In simple terms, traditional drugs are like turning off a machine, while PROTACs are like dismantling the machine altogether. This mechanism provides several unique advantages:

●  Direct elimination of disease-causing proteins rather than temporary inhibition;

●  Catalytic activity that can prolong therapeutic effects;

●  Potential to overcome certain forms of drug resistance;

●  Access to a broader range of previously inaccessible therapeutic targets.

As a result, targeted protein degradation is widely viewed as one of the most promising therapeutic platforms since the emergence of small-molecule and antibody-based drugs.

Global Clinical Development Enters a Rapid Growth Phase

Since the first PROTAC drugs entered human clinical trials in 2019, the field of targeted protein degradation has advanced rapidly.

U.S.-based biotechnology company Arvinas is one of the pioneers in this area. Its candidate ARV-110 was developed for metastatic castration-resistant prostate cancer, while ARV-471 targets estrogen receptor (ER)-positive breast cancer. ARV-471 has already progressed into late-stage clinical development and is considered one of the leading candidates likely to become the first commercially approved PROTAC therapy.

At the same time, companies such as C4 Therapeutics, Kymera Therapeutics, and Nurix have advanced multiple protein degradation programs into clinical studies. Current clinical-stage PROTAC candidates are primarily focused on:

●  Oncology;

●  Autoimmune diseases;

●  Inflammatory disorders;

●  Hematologic malignancies;

●  Neurodegenerative diseases.

Among these areas, oncology has seen the fastest progress, with programs targeting AR, ER, BTK, IKZF1/3, BCL6, and several other high-profile targets.

Beyond biotechnology innovators, major pharmaceutical companies including Pfizer, Roche, Novartis, Sanofi, and Merck have also entered the protein degradation field through strategic collaborations, licensing agreements, and investments. The value of related partnerships has continued to rise in recent years, reflecting strong industry confidence in the technology.

Chinese Pharmaceutical Companies Are Emerging as Key Players

Driven by the global PROTAC boom, Chinese biopharmaceutical companies have rapidly expanded their presence in the field. Unlike the early days when development relied heavily on imported technologies, Chinese companies are now building proprietary protein degradation platforms and advancing original programs into clinical trials.

Representative companies active in the PROTAC space include Hengrui Pharma, Haisco, Kintor Pharmaceutical, Gan & Lee Pharmaceuticals, Qilu Pharmaceutical, and several innovative biotechnology startups.

More importantly, a growing number of Chinese innovators are tackling some of the world’s most challenging targets. KRAS G12D, for example, has long been considered one of the most difficult targets in oncology. Several Chinese-developed PROTAC candidates have already received clinical trial approvals in both China and the United States, demonstrating increasing global competitiveness.

Overall, China’s PROTAC landscape is characterized by three major trends:

●  Rapid growth in the number of clinical-stage programs;

●  Increasing emphasis on novel and proprietary targets;

●  Greater adoption of global development strategies.

These trends suggest that Chinese companies are gradually evolving from followers to competitors—and in some areas, even potential leaders—in the global protein degradation arena.

Challenges Remain Despite Enormous Potential

Although the outlook is highly promising, several technical hurdles must still be overcome before PROTACs achieve widespread commercialization.

The first challenge is pharmacokinetics. Because PROTACs are composed of multiple functional modules, their molecular weights are typically much larger than those of conventional small-molecule drugs. This can lead to reduced oral absorption, limited tissue penetration, and stability issues.

The second challenge is the limited availability of E3 ligases. While the human body contains hundreds of E3 ligases, most clinical-stage PROTACs currently rely on only a few, such as CRBN and VHL. Identifying additional tissue-specific E3 ligases will be crucial for expanding the technology’s future applications.

Researchers must also address several other issues:

●  Off-target degradation risks;

●  Long-term safety validation;

●  Potential resistance mechanisms;

●  Manufacturing and process optimization for complex molecules.

These challenges indicate that PROTAC technology is still in a developmental stage, but they do not diminish its long-term promise.

The Era of Targeted Protein Degradation Is Approaching

Historically, every transformative technology has progressed through three stages: proof of concept, clinical validation, and commercial expansion. PROTACs have already completed the proof-of-concept phase and are now moving toward critical clinical validation.

As more candidates advance into Phase II and Phase III trials, the global pharmaceutical industry is closely watching to see when the first PROTAC therapy will receive regulatory approval. A successful launch would not only validate targeted protein degradation as a new therapeutic paradigm but could also unlock vast opportunities among previously undruggable targets.

Looking ahead, PROTAC is more than just a technological innovation—it has the potential to reshape the entire pharmaceutical ecosystem. As more breakthrough therapies reach the market, stakeholders across the value chain, from research organizations to pharmaceutical distributors, will participate in this transformation. Pharmaceutical commerce companies such as Dengyue Pharmaceutical are also expected to witness the market opportunities created by the emerging era of targeted protein degradation.