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This report is written by MaltSci based on the latest literature and research findings

What are the applications of PROTACs in targeted protein degradation? ​

Abstract ​

The emergence of Proteolysis Targeting Chimeras (PROTACs) has revolutionized the field of targeted protein degradation, presenting a novel therapeutic strategy that extends beyond traditional small-molecule inhibitors. PROTACs utilize the ubiquitin-proteasome system to selectively degrade disease-associated proteins, thus addressing the limitations of conventional therapies, particularly in oncology and neurodegenerative diseases. This review highlights the unique mechanisms of PROTACs, emphasizing their bifunctional nature, which allows them to bind simultaneously to target proteins and E3 ubiquitin ligases, facilitating the degradation of proteins that contribute to disease pathogenesis. Recent advancements in PROTAC technology have demonstrated their efficacy in targeting oncogenic proteins, overcoming drug resistance, and degrading aggregated proteins linked to neurodegenerative disorders. The potential applications of PROTACs are broad, encompassing cancer therapy, autoimmune diseases, and viral infections. However, challenges related to pharmacokinetics, off-target effects, and safety concerns must be addressed to enhance their clinical viability. Ongoing research is focused on optimizing PROTAC design and expanding their therapeutic applications, positioning PROTACs as a promising avenue for innovative drug discovery and development.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Mechanisms of PROTACs
    • 2.1 Structure and Function of PROTACs
    • 2.2 Mechanistic Pathways in Targeted Protein Degradation
  • 3 Applications of PROTACs in Cancer Therapy
    • 3.1 PROTACs Targeting Oncogenic Proteins
    • 3.2 Overcoming Resistance in Cancer Treatment
  • 4 PROTACs in Neurodegenerative Diseases
    • 4.1 Targeting Aggregated Proteins
    • 4.2 Potential for Treating Alzheimer's and Parkinson's Disease
  • 5 Challenges and Limitations
    • 5.1 Pharmacokinetics and Biodistribution
    • 5.2 Off-Target Effects and Safety Concerns
  • 6 Future Directions
    • 6.1 Advances in PROTAC Design
    • 6.2 Expanding Target Range and Therapeutic Applications
  • 7 Conclusion

1 Introduction ​

The field of targeted protein degradation has witnessed significant advancements in recent years, with the emergence of Proteolysis Targeting Chimeras (PROTACs) as a groundbreaking therapeutic strategy. PROTACs are heterobifunctional molecules that utilize the ubiquitin-proteasome system to selectively degrade disease-associated proteins, offering a unique approach that differs fundamentally from traditional small molecule inhibitors. Instead of merely inhibiting the function of target proteins, PROTACs induce their degradation, thereby modulating protein levels within cells. This innovative mechanism has profound implications for treating various diseases, including cancer, neurodegenerative disorders, and autoimmune diseases [1][2].

The significance of PROTACs lies in their ability to target proteins that are traditionally considered "undruggable," such as those lacking enzymatic activity or possessing challenging structural characteristics. This capability allows for the selective elimination of proteins implicated in disease processes, thus presenting a promising avenue for therapeutic intervention. Moreover, PROTACs can overcome common issues associated with conventional therapies, such as drug resistance and off-target effects, by engaging the cell's intrinsic protein degradation machinery [3][4].

Current research on PROTACs has accelerated, with numerous studies demonstrating their efficacy across a wide range of therapeutic areas. A growing number of PROTACs are entering clinical trials, showcasing their potential to transform drug discovery and therapeutic development [5][6]. For instance, recent advancements have highlighted the use of PROTACs in cancer therapy, where they have shown promise in targeting oncogenic proteins and overcoming treatment resistance [2][7]. Additionally, PROTACs are being explored for their potential in neurodegenerative diseases, where they can target aggregated proteins associated with conditions such as Alzheimer's and Parkinson's disease [4][6].

This review aims to provide a comprehensive overview of the applications of PROTACs in targeted protein degradation, organized into several key sections. First, we will delve into the mechanisms of PROTACs, detailing their structure and function, as well as the mechanistic pathways involved in targeted protein degradation. Next, we will explore the diverse applications of PROTACs in cancer therapy, focusing on their ability to target oncogenic proteins and their potential to overcome resistance mechanisms. Following this, we will discuss the role of PROTACs in neurodegenerative diseases, emphasizing their capability to address the challenges posed by aggregated proteins.

In addition to the applications, we will also address the challenges and limitations associated with the clinical translation of PROTACs, including pharmacokinetics, biodistribution, and safety concerns. Finally, we will outline future directions in this rapidly evolving field, highlighting advances in PROTAC design and the expansion of their therapeutic applications. By synthesizing current knowledge and insights, this review seeks to underscore the transformative potential of PROTACs in drug discovery and to stimulate further research in this innovative area of biomedical science [1][8].

2 Mechanisms of PROTACs ​

2.1 Structure and Function of PROTACs ​

Proteolysis-targeting chimeras (PROTACs) represent a novel therapeutic approach in targeted protein degradation, leveraging the ubiquitin-proteasome system (UPS) to selectively degrade specific proteins associated with various diseases. The applications of PROTACs are extensive, particularly in cancer therapy, as they offer several advantages over traditional small-molecule inhibitors.

Applications of PROTACs in Targeted Protein Degradation:

PROTACs have emerged as a promising strategy in drug discovery, particularly for targeting "undruggable" proteins that conventional small molecules cannot effectively inhibit. They have been shown to degrade various oncoproteins involved in cancer, thus providing a novel means of therapy. PROTACs can target proteins that are overexpressed or mutated, which are often responsible for drug resistance in cancer treatments. This capability allows for the degradation of proteins that are critical for tumor survival, offering a new angle for therapeutic intervention [3][6][7].

Additionally, PROTACs have applications beyond oncology, including potential treatments for autoimmune diseases, neurodegenerative disorders, and viral infections. Their ability to induce the degradation of specific proteins involved in these conditions opens avenues for innovative therapies that can circumvent existing resistance mechanisms and improve treatment specificity [2][4][5].

Mechanisms of PROTACs:

The mechanism of action of PROTACs involves the formation of a ternary complex comprising the target protein, the PROTAC molecule, and an E3 ubiquitin ligase. The bifunctional nature of PROTACs enables them to bind simultaneously to the target protein and the E3 ligase, facilitating the ubiquitination of the target protein, which subsequently leads to its degradation by the proteasome [1][8][9]. This mechanism not only results in the elimination of the target protein but also circumvents the need for continuous drug occupancy, allowing for catalytic degradation and prolonged pharmacodynamic effects [2][10].

Structure and Function of PROTACs:

Structurally, PROTACs are heterobifunctional molecules composed of three key components: a ligand that binds to the target protein, a linker that connects the two ligands, and a ligand that recruits an E3 ubiquitin ligase [1][6]. The design of PROTACs requires careful consideration of the linker length and composition, as these factors significantly influence the efficacy and specificity of the degradation process [11][12].

The functional capabilities of PROTACs are enhanced by their ability to degrade a wide range of proteins, including those previously deemed "undruggable." For instance, PROTACs can effectively target transcription factors and scaffolding proteins that play critical roles in disease pathogenesis [2][5]. This versatility, combined with the potential for reduced off-target effects, makes PROTACs a compelling tool in therapeutic development [3][4].

In summary, PROTACs represent a transformative approach in targeted protein degradation, with applications spanning cancer therapy and beyond. Their unique mechanism of action, structural design, and functional capabilities position them as a powerful class of therapeutics that can address significant challenges in modern medicine.

2.2 Mechanistic Pathways in Targeted Protein Degradation ​

Proteolysis-targeting chimeras (PROTACs) represent a groundbreaking approach in the field of targeted protein degradation, utilizing the ubiquitin-proteasome system to selectively degrade specific proteins associated with various diseases, particularly cancer. The mechanism of action of PROTACs is fundamentally distinct from traditional small-molecule inhibitors, as they do not merely inhibit protein function but instead promote the complete degradation of the target protein. This unique capability is attributed to their bifunctional design, which consists of two ligands: one that binds to the target protein and another that recruits an E3 ubiquitin ligase, facilitating ubiquitination and subsequent proteasomal degradation of the target protein.

The applications of PROTACs are vast and encompass several disease contexts. In oncology, PROTACs have shown great promise in targeting "undruggable" oncoproteins, which are often resistant to conventional therapeutic strategies. For instance, PROTACs have been developed to target proteins such as BTK, BRD4, and various hormone receptors, demonstrating significant efficacy in preclinical models and early-phase clinical trials (Li et al., 2022; Venkatesan et al., 2022). This capability to degrade proteins rather than inhibit them allows PROTACs to overcome challenges associated with drug resistance, a common hurdle in cancer treatment.

Furthermore, PROTACs are being explored beyond oncology, with applications in neurodegenerative diseases, viral infections, and autoimmune disorders. For example, researchers have identified potential PROTACs targeting proteins involved in Alzheimer's disease, leveraging their ability to degrade proteins that are traditionally difficult to target with small molecules (Xie et al., 2023). The adaptability of PROTAC technology allows for the degradation of various types of proteins, including enzymes, transcription factors, and structural proteins, thereby broadening the therapeutic landscape.

The mechanistic pathways involved in PROTAC-mediated degradation hinge on their interaction with the ubiquitin-proteasome system. Upon binding to the target protein, the PROTAC facilitates the recruitment of an E3 ubiquitin ligase, which catalyzes the transfer of ubiquitin molecules to the target protein. This ubiquitination signals the protein for degradation by the 26S proteasome, effectively removing it from the cellular environment. The cyclical nature of this process allows for sustained degradation, as a single PROTAC molecule can catalyze the degradation of multiple target proteins (Neklesa et al., 2017).

Moreover, recent advancements in PROTAC design have focused on enhancing their pharmacokinetic properties and reducing off-target effects. Innovations such as conditional PROTACs, which can be activated in specific cellular contexts, aim to improve the precision of targeted protein degradation (Yim et al., 2024). Additionally, the development of PROTACs that utilize different E3 ligases, such as VHL and CRBN, has expanded the repertoire of targetable proteins, further enhancing their therapeutic potential (Zhang et al., 2025).

In summary, PROTACs represent a transformative strategy in drug discovery and therapeutic development, with applications spanning cancer therapy, neurodegenerative diseases, and beyond. Their unique mechanism of action not only allows for the degradation of previously deemed "undruggable" proteins but also offers a means to circumvent common issues of drug resistance. The ongoing research and clinical trials will likely elucidate further potential applications and refine the mechanisms of PROTACs, paving the way for innovative treatments in various disease contexts [5][6][7].

3 Applications of PROTACs in Cancer Therapy ​

3.1 PROTACs Targeting Oncogenic Proteins ​

Proteolysis-targeting chimeras (PROTACs) represent a groundbreaking advancement in targeted protein degradation, particularly in the realm of cancer therapy. Their ability to selectively degrade oncogenic proteins positions them as a transformative tool in oncology, addressing limitations associated with traditional small-molecule inhibitors. The applications of PROTACs in targeting oncogenic proteins are multifaceted and significant.

One of the primary applications of PROTACs is their capacity to induce the degradation of tumor-overexpressing oncogenic proteins through the recruitment of E3 ligases, utilizing the ubiquitin-proteasome system (UPS) for this purpose. This mechanism allows PROTACs to catalyze the degradation of proteins that are often considered "undruggable" by conventional methods, thereby expanding the therapeutic landscape for cancer treatment (Moon et al. 2023; Anaya et al. 2025). For instance, PROTACs can effectively target proteins that have historically posed challenges in drug development due to their structural properties or lack of suitable binding sites.

The versatility of PROTACs also enables them to tackle a wide array of oncogenic proteins implicated in various malignancies. They can specifically target proteins involved in critical cancer pathways, thus facilitating a more nuanced approach to therapy that can be tailored to the specific molecular characteristics of a patient's tumor (Li et al. 2022). For example, PROTACs have been developed to target proteins like BRD4, which plays a pivotal role in the regulation of gene expression and is overexpressed in several cancers (Gao et al. 2025).

Moreover, the bifunctional nature of PROTACs allows for sustained target suppression with lower doses, potentially leading to reduced toxicity compared to traditional inhibitors (Rutherford & McManus 2024). This catalytic mechanism not only enhances the efficacy of cancer treatments but also helps mitigate the risk of drug resistance, a common challenge faced in oncology (Lin et al. 2025).

Recent advancements have also seen the integration of PROTACs with innovative delivery systems to enhance their therapeutic potential. This integration aims to improve pharmacokinetics, bioavailability, and tumor targeting, which are critical for the effective clinical application of PROTACs (Liu et al. 2025; Zhang et al. 2025). Various strategies, such as nanoparticle-based delivery and the development of tissue-selective PROTACs, are being explored to maximize their efficacy while minimizing off-target effects (Meng et al. 2025).

In conclusion, the applications of PROTACs in targeting oncogenic proteins are profound and continue to evolve. Their ability to selectively degrade critical cancer-related proteins positions them as a promising strategy in precision medicine, potentially leading to more effective and personalized cancer therapies. The ongoing research and clinical trials involving PROTACs underscore their significant role in the future of cancer treatment, offering hope for improved outcomes for patients with malignancies.

3.2 Overcoming Resistance in Cancer Treatment ​

Proteolysis-targeting chimeras (PROTACs) have emerged as a revolutionary approach in targeted protein degradation, particularly within the realm of cancer therapy. Their innovative mechanism allows for the selective degradation of oncogenic proteins, which are often deemed "undruggable" by traditional small-molecule inhibitors. This capability positions PROTACs as a promising strategy to address the significant challenge of drug resistance encountered in cancer treatments.

One of the primary applications of PROTACs is their ability to overcome resistance mechanisms that typically thwart the efficacy of conventional therapies. Cancer cells often develop resistance through various means, such as mutations in target proteins, upregulation of drug efflux pumps, or activation of alternative signaling pathways. PROTACs circumvent these challenges by inducing the complete degradation of target proteins rather than merely inhibiting their function. This is particularly advantageous as it allows for the elimination of mutated or overexpressed proteins that contribute to resistance, thereby restoring sensitivity to treatment [5][7][13].

Furthermore, PROTACs have demonstrated efficacy against a range of oncogenic targets associated with different malignancies, including prostate, breast, and hematological cancers. Their modular design enables the targeting of multiple proteins simultaneously, enhancing therapeutic outcomes and reducing the likelihood of resistance development. This is particularly significant in complex cancers where multiple pathways may be activated to promote survival and proliferation [10][14][15].

Recent studies have also highlighted the potential of PROTACs in addressing specific challenges associated with cancer drug resistance. For instance, PROTACs have been shown to effectively degrade proteins that are responsible for resistance to first-line therapies, providing a novel means to restore sensitivity in heavily pretreated patient populations [6][16]. Additionally, the catalytic nature of PROTACs allows for the degradation of target proteins at lower concentrations, which can minimize off-target effects and systemic toxicity, thus improving the therapeutic index [17][18].

The ongoing research and development of PROTACs are also expanding their applications beyond traditional cancer therapies. For example, PROTACs are being explored in the context of immunotherapy, where they may enhance the efficacy of immune checkpoint inhibitors by degrading immunosuppressive proteins within the tumor microenvironment [5][19]. This dual approach of targeting both cancer cells and the surrounding immunosuppressive milieu represents a significant advancement in cancer treatment strategies.

In conclusion, PROTACs are paving the way for next-generation cancer therapies by providing a robust platform for targeted protein degradation. Their unique ability to overcome drug resistance, coupled with their application in various malignancies, underscores their potential to revolutionize cancer treatment paradigms. As research progresses, the integration of PROTACs into clinical practice may offer new hope for patients facing treatment-resistant cancers, thereby enhancing the overall efficacy of cancer therapies [5][14][15].

4 PROTACs in Neurodegenerative Diseases ​

4.1 Targeting Aggregated Proteins ​

Proteolysis-targeting chimeras (PROTACs) represent a novel and promising approach in the field of targeted protein degradation, particularly in the context of neurodegenerative diseases characterized by the accumulation of aggregated proteins. These aggregates, often composed of misfolded proteins, pose significant challenges for conventional treatment methods, as they are typically resistant to small-molecule inhibitors.

One of the primary applications of PROTACs in neurodegenerative diseases is their ability to selectively target and degrade pathogenic proteins associated with these conditions. Recent studies have demonstrated that PROTACs can effectively induce the degradation of proteins implicated in diseases such as Alzheimer's and Parkinson's disease. For instance, they can target aggregates formed by proteins like tau and alpha-synuclein, which are known to contribute to the pathogenesis of these disorders. By facilitating the removal of these toxic aggregates, PROTACs may help to alleviate the associated neurodegenerative processes and improve cognitive and motor functions.

The advantages of PROTACs in this context stem from their unique mechanism of action, which allows for the complete degradation of target proteins rather than mere inhibition of their activity. This is particularly beneficial for addressing the "undruggable" proteome, which includes many proteins involved in neurodegenerative diseases that cannot be effectively targeted by traditional small-molecule drugs. PROTACs leverage the ubiquitin-proteasome system to tag these proteins for degradation, thus overcoming the limitations faced by conventional therapies[20][21].

Moreover, the development of PROTACs tailored for specific E3 ligases presents further opportunities for enhancing their therapeutic potential. By designing PROTACs that can selectively engage different E3 ligases, researchers can optimize the degradation of specific aggregated proteins, potentially leading to more effective treatments for neurodegenerative diseases[22].

However, challenges remain in the practical application of PROTACs for neurodegenerative diseases. Key issues include the molecular design of these degrader molecules to ensure efficient delivery across the blood-brain barrier and the need for improved selectivity to minimize off-target effects. Ongoing research aims to address these challenges, exploring novel formats of PROTACs and alternative delivery systems to enhance their therapeutic efficacy in the central nervous system[4][20].

In summary, PROTACs hold significant promise as a therapeutic strategy for neurodegenerative diseases by targeting and degrading aggregated proteins that contribute to disease pathology. Their unique mechanism of action, combined with ongoing advancements in molecular design and delivery systems, positions PROTACs as a potentially transformative approach in the treatment of these challenging disorders.

4.2 Potential for Treating Alzheimer's and Parkinson's Disease ​

Proteolysis-targeting chimeras (PROTACs) represent a novel and promising approach in the field of targeted protein degradation, particularly in the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). These disorders are characterized by the accumulation of misfolded and aggregated proteins, which contribute significantly to neuronal dysfunction and cell death. The ability of PROTACs to selectively degrade these aberrant proteins offers a transformative strategy for addressing the underlying pathologies of these diseases.

PROTACs utilize the ubiquitin-proteasome system to induce the degradation of specific target proteins. This technology allows for the catalytic degradation of proteins, which can include those that are traditionally considered "undruggable" due to their structural properties or lack of suitable binding sites for small molecules. For instance, recent studies have highlighted the potential of PROTACs to target proteins such as Tau and α-synuclein, which are critically involved in the pathogenesis of AD and PD, respectively. By promoting the degradation of these toxic proteins, PROTACs could mitigate their harmful effects and potentially slow the progression of neurodegenerative diseases [23].

Research has shown that PROTACs can effectively target and degrade mutant forms of proteins associated with neurodegenerative conditions, including mutant huntingtin (mHTT) in Huntington's disease and tau protein in Alzheimer's disease. This targeted approach not only reduces the levels of these harmful proteins but also allows for a more precise modulation of protein homeostasis within neuronal cells [24].

The clinical implications of PROTAC technology in neurodegenerative diseases are significant. As the current therapeutic options for AD and PD are limited and often ineffective in halting disease progression, the development of PROTACs represents a new frontier in drug discovery. PROTACs have shown the ability to achieve effective protein degradation at low concentrations, allowing for fine-tuned control over protein levels. This is particularly important in neurodegenerative diseases, where maintaining a delicate balance of protein expression is crucial for neuronal health [20].

However, the application of PROTACs in treating neurodegenerative diseases is not without challenges. Key issues include enhancing the oral bioavailability of PROTACs and ensuring their ability to cross the blood-brain barrier, which is essential for targeting central nervous system proteins. Current research is focused on overcoming these barriers, with ongoing studies exploring novel PROTAC designs and delivery mechanisms [25].

In summary, PROTAC technology holds substantial promise for the treatment of neurodegenerative diseases, particularly Alzheimer's and Parkinson's disease, by enabling the targeted degradation of pathogenic proteins. As research continues to advance in this area, PROTACs may offer new therapeutic options that address the unmet clinical needs of patients suffering from these debilitating conditions.

5 Challenges and Limitations ​

5.1 Pharmacokinetics and Biodistribution ​

Proteolysis Targeting Chimeras (PROTACs) represent a transformative approach in the realm of targeted protein degradation, demonstrating significant potential across various therapeutic applications, particularly in oncology. These bifunctional molecules leverage the ubiquitin-proteasome system (UPS) to selectively degrade disease-associated proteins, including those traditionally classified as "undruggable" due to their complex structures or essential roles in cellular processes.

Applications of PROTACs in Targeted Protein Degradation ​

The primary application of PROTACs is in the treatment of cancer, where they target overexpressed oncogenic proteins, thereby inducing apoptosis in malignant cells. PROTACs have shown efficacy against various oncoproteins such as BCL6, STAT3, and BRD4, and are being explored in clinical trials for their therapeutic activity against multiple cancer types, including metastatic castration-resistant prostate cancer (mCRPC) and non-small cell lung cancer (NSCLC) [13][26]. Beyond oncology, PROTACs are also being investigated for their potential in treating autoimmune diseases, neurodegenerative disorders, and viral infections, highlighting their broad applicability [8].

Moreover, the modular design of PROTACs allows for systematic optimization and rational design, enhancing their tissue distribution properties and enabling the targeting of proteins that are overexpressed in specific disease states [26]. This versatility has garnered considerable attention from researchers and pharmaceutical companies, positioning PROTACs as a promising tool in drug discovery and development [27].

Challenges and Limitations ​

Despite their potential, the development and clinical application of PROTACs face several challenges. One significant limitation is their pharmacokinetic properties, particularly their poor solubility and low cellular permeability, which can hinder effective delivery to target tissues [13]. Additionally, systemic toxicity is a concern, as PROTACs may inadvertently degrade non-target proteins, leading to off-target effects [13].

Another challenge is the dependency on E3 ligases for the mechanism of action. The limited availability and variability of E3 ligases across different tissues can complicate the efficacy and specificity of PROTACs [8]. Furthermore, the potential for acquired resistance, similar to that observed with traditional small-molecule inhibitors, raises concerns about the long-term effectiveness of PROTAC therapies [1].

Pharmacokinetics and Biodistribution ​

The pharmacokinetic (PK) profile of PROTACs is crucial for their therapeutic efficacy. Traditional PROTACs often exhibit poor water solubility and low bioavailability, which can limit their therapeutic application [28]. To address these issues, recent strategies have focused on integrating PROTACs with advanced drug delivery systems, such as nanoparticles and covalent modification-based prodrugs, to enhance their in vivo performance [13].

Moreover, the biodistribution of PROTACs can be influenced by their molecular weight and structural characteristics. Research has indicated that modifications to the linker and ligand components of PROTACs can significantly affect their tissue distribution and cellular uptake [28]. Enhanced tissue specificity and reduced off-target effects are critical for improving the clinical viability of PROTACs, and ongoing studies are aimed at optimizing these parameters [5].

In summary, while PROTACs offer a novel approach to targeted protein degradation with significant therapeutic potential, their clinical application is tempered by challenges related to pharmacokinetics, off-target effects, and the reliance on E3 ligases. Continued research into delivery mechanisms and the optimization of PROTAC design is essential for overcoming these limitations and enhancing their therapeutic efficacy in various disease contexts.

5.2 Off-Target Effects and Safety Concerns ​

Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in the field of targeted protein degradation, offering a novel therapeutic approach for various diseases, particularly in oncology. PROTACs function by hijacking the ubiquitin-proteasome system to induce the selective degradation of target proteins, which has made them a promising tool in drug discovery and development.

The applications of PROTACs are diverse, encompassing a wide range of diseases, especially cancer. They have shown the ability to degrade "undruggable" proteins that traditional small-molecule inhibitors cannot effectively target, thereby expanding the scope of potential therapeutic targets. For instance, PROTACs have successfully been utilized to degrade various proteins such as Bruton's tyrosine kinase (BTK), estrogen receptor (ER), and androgen receptor (AR), which are crucial in the pathology of certain cancers [2][8][29]. Furthermore, ongoing clinical trials indicate their efficacy in treating conditions like metastatic castration-resistant prostate cancer (mCRPC) and other malignancies [5][26].

Despite their promising applications, the use of PROTACs is not without challenges and limitations. One of the primary concerns is the occurrence of off-target effects, which can lead to unintended degradation of non-target proteins. This can result in significant side effects, especially when PROTACs are administered systemically. The selectivity of PROTACs is crucial, as off-target degradation may affect healthy cells, leading to toxicity [30][31]. Additionally, the large molecular weight of PROTACs can impede their membrane permeability, further complicating their therapeutic application [29].

Safety concerns also arise from the potential for systemic toxicity due to the non-specific degradation of proteins that play vital roles in normal cellular functions. The degradation of these proteins can disrupt homeostasis and lead to adverse effects [31][32]. To address these issues, researchers are exploring innovative strategies, such as developing conditional PROTACs that are activated only in the presence of specific stimuli, thus enhancing their selectivity and reducing off-target effects [33][34].

In summary, while PROTACs hold great promise in the field of targeted protein degradation, their clinical application is hindered by challenges related to off-target effects and safety concerns. Ongoing research is focused on optimizing the design and delivery of PROTACs to improve their specificity and minimize potential side effects, thereby enhancing their therapeutic efficacy in treating various diseases.

6 Future Directions ​

6.1 Advances in PROTAC Design ​

Proteolysis-targeting chimeras (PROTACs) represent a significant advancement in the field of targeted protein degradation, offering innovative applications across various therapeutic areas. These bifunctional molecules leverage the ubiquitin-proteasome system to induce selective degradation of specific proteins, including those traditionally considered "undruggable." The versatility of PROTACs allows for their application in multiple diseases, including cancer, autoimmune disorders, neurodegenerative diseases, and viral infections, among others.

In cancer therapy, PROTACs have emerged as a promising strategy to degrade oncoproteins that drive tumorigenesis. They facilitate the elimination of proteins that are often resistant to conventional small-molecule inhibitors, thus overcoming challenges related to drug resistance and improving therapeutic outcomes [6][7]. The ability of PROTACs to degrade non-enzymatic and structural proteins further enhances their therapeutic potential, as they can target a broader range of proteins than traditional inhibitors [3].

Recent advancements in PROTAC design have focused on addressing limitations associated with conventional PROTACs, such as poor solubility and off-target toxicity. Researchers have developed unconventional PROTACs with novel binding ligands and linkers, pro-PROTACs, and self-assembled PROTACs to enhance their efficacy and specificity [5]. Additionally, the introduction of stimuli-activated PROTACs aims to improve the precision of protein degradation, thereby minimizing potential side effects [33].

The ongoing evolution of PROTAC technology also encompasses the development of various platforms that expand the scope of targetable proteins. For instance, the LipoSM-PROTAC platform utilizes liposome self-assembly to achieve effective protein degradation in vivo [35]. Furthermore, innovative approaches such as conditional PROTACs, which modulate protein degradation in a spatio-temporal manner, have been explored to enhance targeting specificity and therapeutic precision [34].

Future directions in PROTAC research are likely to include the identification of additional E3 ligases that can be harnessed for targeted degradation, as well as the optimization of PROTAC pharmacokinetics and pharmacodynamics to improve their clinical applicability [8]. The integration of machine learning techniques to predict the degradability of proteins and to guide the design of new PROTACs is also a promising avenue for advancing this technology [12].

In summary, the applications of PROTACs in targeted protein degradation span a wide array of diseases, with ongoing advancements in their design aimed at enhancing efficacy, specificity, and therapeutic potential. The evolution of this technology holds significant promise for the development of novel therapeutics that can effectively target previously challenging protein substrates.

6.2 Expanding Target Range and Therapeutic Applications ​

Proteolysis-targeting chimeras (PROTACs) represent a groundbreaking approach in targeted protein degradation, leveraging the ubiquitin-proteasome system to selectively degrade proteins implicated in various diseases. The applications of PROTACs extend across multiple therapeutic areas, particularly in oncology, neurodegenerative diseases, and inflammatory disorders, with ongoing research aimed at broadening their target range and enhancing their clinical utility.

In oncology, PROTACs have shown significant promise by targeting "undruggable" proteins that are often resistant to conventional small-molecule inhibitors. For instance, PROTACs can effectively degrade oncoproteins that contribute to tumorigenesis, thus offering a novel strategy to combat cancer where traditional therapies fail (Malarvannan et al. 2025; Casan & Seymour 2024). The ability of PROTACs to induce complete protein degradation rather than merely inhibiting their function provides a distinct advantage, potentially circumventing issues related to drug resistance commonly observed with small-molecule therapies (Casan & Seymour 2024).

Beyond cancer, PROTACs are being explored for their therapeutic potential in neurodegenerative diseases, where the accumulation of misfolded or toxic proteins contributes to pathogenesis. Recent studies indicate that PROTACs can target such aberrant proteins for degradation, thereby alleviating cellular toxicity and improving neuronal health (Wang et al. 2024). Furthermore, there is growing interest in applying PROTAC technology to treat autoimmune disorders and viral infections, where the targeted degradation of specific proteins involved in disease pathways could lead to innovative therapeutic options (Tamatam & Shin 2023; Wang et al. 2024).

Future directions for PROTAC technology focus on expanding the range of druggable targets and improving the specificity and efficiency of these agents. Researchers are investigating advanced PROTAC designs, including those that utilize stimuli-responsive mechanisms to enhance spatial and temporal control over protein degradation. Such innovations aim to minimize off-target effects and improve the therapeutic index of PROTACs (Yim et al. 2024; Zhang et al. 2025). Additionally, there is a concerted effort to develop new classes of PROTACs, such as nano-PROTACs and biomacromolecule-PROTAC conjugates, which could enhance delivery and efficacy in vivo (Wang et al. 2024; Malarvannan et al. 2025).

In summary, the applications of PROTACs in targeted protein degradation are diverse and expanding. As research continues to evolve, the integration of novel design strategies and therapeutic applications is expected to significantly enhance the potential of PROTACs as a transformative tool in modern medicine, addressing a wide array of diseases previously deemed difficult to treat.

7 Conclusion ​

The applications of Proteolysis Targeting Chimeras (PROTACs) in targeted protein degradation have emerged as a transformative strategy in modern medicine, particularly in the realms of oncology and neurodegenerative diseases. PROTACs offer a unique mechanism that not only inhibits but actively degrades target proteins, including those traditionally considered 'undruggable.' Their ability to circumvent common issues such as drug resistance positions them as a promising avenue for therapeutic intervention. Current research highlights their efficacy in degrading oncogenic proteins, thus enhancing cancer treatment, and targeting aggregated proteins associated with neurodegenerative disorders, potentially alleviating their detrimental effects. However, challenges remain, particularly concerning pharmacokinetics, off-target effects, and safety. Future directions should focus on optimizing PROTAC design to improve their specificity and efficacy, expanding their therapeutic applications beyond oncology, and exploring innovative delivery systems. As research progresses, PROTACs may revolutionize treatment paradigms across a wide array of diseases, offering hope for improved patient outcomes in previously challenging conditions.

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