Introduction
Targeted Protein Degradation (TPD) is an emerging therapeutic approach that has gained significant attention because it can regulate proteins traditionally considered “undruggable” by small molecules. PROTACs (Proteolysis-Targeting Chimeras) harness the cell’s natural protein degradation system—the ubiquitin-proteasome system (UPS)—to achieve targeted degradation of proteins of interest (POIs). As PROTAC pipelines expand into oncology, in vitro drug combination screening is increasingly used to evaluate how degraders synergize with targeted therapies and immuno-oncology agents.
A PROTAC is a heterobifunctional small molecule: one end binds to the POI, and the other recruits an E3 ubiquitin ligase, forming a dumbbell-shaped ternary complex. The POI is tagged with ubiquitin, then recognized and degraded by the proteasome.
Since the concept of PROTACs was first reported 20 years ago—leveraging the ubiquitin-proteasome system to degrade target proteins—TPD has shifted from academia to industry. Many companies have launched preclinical and early clinical development programs. In 2019, the first PROTACs entered clinical trials. By 2020, clinical proof of concept was achieved against estrogen receptor (ER) and androgen receptor (AR) cancer targets. With this success, TPD is now poised to tackle targets once thought “undruggable.”
I. Overview of PROTACs
The PROTAC concept was first proposed by Crews and colleagues in 2001. Unlike traditional inhibitors that block protein activity, PROTACs leverage the body’s natural protein clearance system to reduce protein levels, thereby treating disease.
Ubiquitin-dependent proteolysis is the main pathway for degrading intracellular proteins and is essential for normal cellular physiology. This process occurs in three steps involving ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3). These enzymes coordinate the transfer of ubiquitin molecules to target proteins (substrates).
Image A PROTAC consists of three parts: (1) a ligand that binds the target protein, (2) a ligand that binds an E3 ligase, and (3) a linker connecting them. Its mechanism is straightforward: it brings the target protein and E3 ligase together. Once the ternary complex is formed, ubiquitin is transferred to the POI, which is then recognized and degraded by the proteasome.
II. Advantages of PROTACs
- Catalytic degradation: Unlike traditional inhibitors, which bind one-to-one with their target, a single PROTAC can degrade multiple protein molecules. This catalytic effect means strong efficacy at low doses. Even if only small amounts of PROTAC remain inside cells, therapeutic effects can persist.
- Bypassing the need for high binding affinity at active sites: Traditional small molecules or antibodies require high concentrations to block activity at specific protein sites. PROTACs, however, induce degradation rather than inhibit function. They only require sufficient binding—not necessarily to active sites—broadening the range of druggable proteins, including those previously deemed undruggable.
- Overcoming drug resistance: Many resistances arise when cells synthesize excess target proteins. Since PROTACs destroy the protein itself, they can overcome such resistance mechanisms.
In short, PROTAC technology combines the advantages of small-molecule drugs, biologics, and RNAi approaches, making it a key candidate for the next wave of blockbuster therapies.
III. Development of PROTACs
The first PROTAC era began with a landmark 2001 study by Sakamoto et al., demonstrating proof of concept in vitro. Protac-1 targeted methionine aminopeptidase 2 (METAP2), a validated anti-angiogenesis target. Protac-1 linked ovalicin to a 10-amino-acid phosphopeptide from IκBα, recognized by the E3 ligase β-TRCP. This bridged METAP2 and β-TRCP, enabling ubiquitination of METAP2.
Image Later, a peptide derived from hypoxia-inducible factor-1α (HIF1α) was shown to bind the VHL E3 ligase, enabling design of cell-permeable PROTACs that degrade multiple POIs. These early designs—containing peptide-based E3 ligase ligands—are now termed “bioPROTACs.” The discovery of small-molecule mimetics of the HIF1α peptide opened the door to fully small-molecule PROTACs. From there, the field grew exponentially.
In 2019, ARV-110 became the first PROTAC to enter clinical trials, ending the “foundational era” of TPD. ARV-110 degrades AR by recruiting it to the CRL4–CRBN ligase complex. Since then, PROTACs have entered a “clinical translation era,” with multiple molecules targeting disease-driving proteins advancing into clinical testing.
IV. Clinical Validation of PROTACs
Before PROTACs entered clinical trials, key questions remained: Would they behave like drugs? Would they be safe in humans? Would they degrade intended targets? Would they show clinical benefit?
Encouragingly, early 2020 Phase I trial results for ARV-110 and ARV-471 answered all four questions positively.
ARV-110 was evaluated in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) (NCT03888612). AR is a known driver of prostate cancer, particularly in treatment-resistant patients with limited options due to anti-androgen resistance. Data showed ARV-110 was well-tolerated up to 420 mg and demonstrated target degradation in tumors—the first molecular evidence of PROTAC activity in humans—with signs of antitumor activity. These findings support further Phase II development.
Similarly, ARV-471 entered trials for ER-positive locally advanced or metastatic breast cancer. Interim data showed good tolerability and strong clinical activity: a 42% clinical benefit rate in heavily pretreated patients, with ER degradation superior to fulvestrant and other selective ER degraders. ARV-471 has advanced to Phase II (NCT04072952) as monotherapy in metastatic breast cancer, with a Phase Ib study combining it with palbociclib underway.
These early results demonstrated favorable safety, pharmacokinetics, and meaningful efficacy, validating the therapeutic feasibility of PROTACs. By late 2021, at least 15 PROTAC drug candidates had entered clinical development, with more expected.
V. Current Status of PROTAC Development
With growing maturity, PROTAC technology has attracted numerous biotech companies and investors. Pioneers of the field founded companies to push forward protein degradation platforms. Leading overseas players include Arvinas, C4 Therapeutics, Kymera Therapeutics, Vividion, Nurix, and Oncopia Therapeutics.
- Arvinas (founded in 2013 by Crews): One of the earliest PROTAC-focused companies. Their lead candidates ARV-110 and ARV-471 (in Phase II) target prostate and breast cancer, respectively.
- C4 Therapeutics (founded 2015 by James Bradner): Focused on oncology targets such as IKZF1/3, BRD9, EGFR, BRAF-V600E, RET. Its TORPEDO platform integrates design, synthesis, and activity evaluation. Partnerships with Biogen and Roche reached $415M and $900M, respectively.
- Kymera Therapeutics (founded 2016): Focuses on cancer and immuno-inflammatory diseases, with IRAK4 and STAT3 among its targets. Lead candidate KT-474 is in Phase I. In 2020, Kymera signed a multi-program collaboration with Sanofi, securing $150M upfront and up to $2B in milestones plus royalties.
- Nurix (founded 2009): Specializes in oral degraders, with BTK and CBL-B targets. Leveraging expertise in E3 ligases and its proprietary DELigase platform, Nurix is advancing NX-2127 in Phase I for relapsed/refractory B-cell malignancies.
Besides startups, pharma giants such as Novartis, BMS, and Amgen have joined the field.
China’s PROTAC landscape: Over 20 domestic companies—both biotech and big pharma—are developing PROTACs. Hisun Pharmaceutical was the first in China to launch a clinical trial, placing it in the leading tier. Other key players include Lingke Pharma, Fandy Technology, MeiShi Medicine, Jiangsu Hengrui, Kintor, Chengdu Lead, HaiChuang Pharma, HaiHe Pharma, Linket Bio, Hejing Medicine, Bio-Thera Solutions, InnoCare, WuYuan Bio, Ascentage Pharma, Kelun Pharma, CSPC, Jiaxing Youbo, Shanghai Ruiyin, Suzhou Degan Bio, MultiDomain Bio, and Lunan Pharma. CROs with PROTAC platforms include WuXi AppTec, Pharmaron, and Medicilon.
Conclusion
Over the past 20 years, PROTACs have rapidly evolved as a cutting-edge drug discovery technology. In recent years, they have become a crucial therapeutic modality. Early positive Phase I and II clinical trial results highlight their enormous potential in oncology and beyond.
With vast therapeutic targets and market potential, PROTACs are poised to join small-molecule inhibitors, monoclonal antibodies, and immunotherapies as a major treatment class, benefiting patients worldwide.
References:
- PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022 Jan 18 : 1–20.
