In the field of biopharmaceuticals, the development of innovative drugs has always been a goal that scientists relentlessly pursue. With the continuous advancement of science and technology, a new drug development technology—Proteolysis Targeting Chimeras (PROTACs)—has gradually emerged, offering new hope for disease treatment. The unique advantages and great potential of PROTAC drugs in clinical trials have attracted widespread attention from researchers and pharmaceutical companies worldwide.
Introduction to PROTAC Technology
PROTAC technology is a method that utilizes the cell’s natural ubiquitin-proteasome system to specifically degrade target proteins. A PROTAC molecule consists of three components: a ligand for the target protein, a ligand for the E3 ubiquitin ligase, and a PROTAC linker connecting these two components. The mechanism of action is that the target protein ligand binds to the target protein, the E3 ligase ligand binds to the E3 ligase, and then the E3 ligase transfers ubiquitin molecules to the target protein. Ultimately, the protein is recognized and degraded by the proteasome, achieving specific elimination of the target protein.
Progress of PROTAC Drugs in Clinical Trials
| Target | Drug | Ligase | Company | Status | ROA | Trial number | Disease |
| AR | ARV-110 | CRBN | Arvinas | Phase 2 | Oral | NCT03888612 | MCRPC |
| AR | ARV-766 | CRBN | Arvinas/Novartis | Phase 1/2 | Oral | NCT05067140 | MCRPC |
| AR | CC-94676 (BMS-986365) | CRBN | BMS | Phase 1 | Oral | NCT04428788 | MCRPC |
| AR | HP518 | Undisclosed | Hinova | Phase 1 | Oral | NCT06155084 NCT05223641 | MCRPC |
| AR | AC-176 | Undisclosed | Accutar | Phase 1 | Oral | NCT05673109 NCT05241613 | MCRPC |
| AR | HRS-5041 | Undisclosed | Jiangsu HengRui | Phase 1 | Oral | NCT05942001 | MCRPC |
| ER | ARV-471 | CRBN | Arvinas/Pfizer | Phase 3 | Oral | NCT04072752 | Breast cancer |
| ER | AC682 | CRBN | Accutar Biotech | Phase 1 | Oral | NCT05080842 | Breast cancer |
| ER | HRS-1358 | Undisclosed | Jiangsu HengRui | Phase 1 | Oral | NCT05288270 | Breast cancer |
| Bcl-xL | DT-2216 | VHL | Dialectic Therapeutics | Phase 1a | IV | NCT05203303 | Hematological malignancies, ST |
| IRAK4 | KT-413 | CRBN | Kymera | Phase 1 | IV | NCT05225584 | DLBCL, leukemia |
| STAT3 | KT-333 | VHL | Kymera | Phase 1 | IV | NCT05225584 | Lymphoma, leukemia |
| BTK | NX-2127 | CRBN | Nurix | Phase 1b | Oral | NCT04830137 | B cell malignancies |
| BTK | NX-5948 | CRBN | Nurix | Phase 1 | Oral | NCT05131022 | B cell malignancies |
| BTK | BGB-16673 | CRBN | BeiGene | Phase 1 | Oral | NCT05006716, NCT05297431 | B cell malignancies |
| BTK | HSK-29116 | CRBN | Haisco | Phase 1 | Oral | NCT04861719 | B cell malignancies |
| BTK | ABBV-101 | Undisclosed | AbbVie | Phase 1 | Oral | NCT05573501 | B cell malignancies |
| BTK | AC-676 | Undisclosed | Accutar | Phase 1 | Oral | NCT05780034 | B cell malignancies |
| BRD9 | CFT-8634 | CRBN | C4 Therapeutics | Phase1/2c | Oral | NCT05355753 | Synovial sarcoma |
| BRD9 | FHD-609 | CRBN | Foghorn Therapeutics | Phase 1d | IV | NCT04965753 | Synovial sarcoma |
| BRAF V600E | CFT1946 | CRBN | C4 Therapeutics | Phase 1/2 | Oral | NCT05668585 | NSCLC, melanoma, colorectal, and anaplastic thyroid cancers, BRAF-mutant ST |
| KRAS G12D | ASP3082 | VHL | Astellas | Phase 1 | IV | NCT05382559 | PDAC, NSCLC, ST |
| SMARCA2 | PRT3789 | VHL | Prelude Therapeutics | Phase 1 | IV | NCT05639751 | NSCLC, ST |
| MDM2 | KT-253 | Undisclosed | Kymera | Phase 1 | IV | NCT05757406 | Lymphoma, leukemia, ST |
| TRK | CG001419 | CRBN | Cullgen | Phase 1 | Oral | CTR20227242 | ST |
| EGFR L858R | HSK-40118 | CRBN | Haisco | Phase 1 | IV | NCT06005980 | NSCLC |
| Undisclosed | QLH12016 | Undisclosed | Qilu Pharmaceutical | Phase 1 | Oral | NCT05973194 | Adenocarcinoma of prostate, MCRPC, PC |
| BCL6 | BMS-986458 | Undisclosed | BMS | Phase 1 | Oral | NCT06009539 | Lymphoma |
| BCL6 | ARV-393 | CRBN | Arvinas | Phase 1 | Oral | NCT06397378 | Lymphoma |
Advantages and Potential of PROTAC Drugs
Overcoming the Limitations of Traditional Drugs: Traditional small molecule inhibitors and biologics typically only inhibit the function of target proteins, whereas PROTAC drugs can directly degrade the target proteins, leading to more thorough inhibition of the target. This is especially beneficial for proteins that are difficult to target with traditional methods, such as “undruggable” proteins. PROTAC technology provides a novel solution for these challenges.
Reducing the Risk of Drug Resistance: In the long-term use of traditional drugs, tumor cells often develop resistance through various mechanisms. PROTAC drugs, by degrading target proteins, can simultaneously disrupt multiple proteins associated with drug resistance, thereby reducing the likelihood of resistance. For example, ARV-471 can overcome endocrine resistance caused by estrogen receptor mutations, and HP518 can degrade both wild-type and mutant AR proteins, offering new hope for the treatment of resistant diseases.
Wide Therapeutic Range: In addition to its notable performance in cancer treatment, PROTAC drugs also show potential therapeutic applications in a variety of other diseases, including immune-inflammatory diseases and neurodegenerative diseases. This expands the range of treatment options available to patients in these areas.
Challenges Faced
Drug Design and Optimization: Designing PROTAC molecules with high activity, high selectivity, and favorable pharmacokinetics is not easy. It requires comprehensive consideration of the selection and optimization of the target protein ligand, E3 ligase ligand, and linker to ensure that the drug can effectively recruit E3 ligases and achieve specific degradation of the target protein, while minimizing off-target effects on other proteins.
Safety and Tolerability: Although some PROTAC drugs have shown good safety profiles in clinical trials, as research progresses and sample sizes increase, adverse reactions may still occur. For example, PROTAC drugs may non-specifically degrade proteins in normal tissues, leading to tissue damage or dysfunction. Additionally, the metabolic products of the drug may have potential toxic effects on the human body.
Drug Resistance: While PROTAC drugs can to some extent overcome the drug resistance issues seen with traditional therapies, tumor cells may still develop resistance to PROTAC drugs through new mechanisms, such as reduced target protein expression, altered E3 ligase activity, or decreased drug uptake. Therefore, delaying or overcoming the resistance to PROTAC drugs remains an important challenge to address.