Key advances and application prospects of PROTAC technologies in the next 5 years

Proteolysis Targeting Chimeras (PROTACs) were considered as revolutionary solutions in the discovery and development of drugs during the past two decades. Since the inception of relevant research in 2001, PROTACs have transformed from novel concepts to therapeutic strategies, which showed great potential for the treatment of complicated targets that were undruggable in the past, and the limitations of traditional small-molecule inhibitors could be solved [1]. Additionally, several important improvements were expected to define the novel PROTAC technology in the next 5 years, especially within the aspects of target deconvolution, material science, target landscapes extension, therapeutic indications broadening, and clinical translation.

1. PROTAC probe for the target deconvolution

The development of target deconvolution was one of the most efficient applications of the PROTAC technology. The effect of traditional methods for identifying drug targets was challenging because of their low abundance and untarget proteins, due to the dependent on high-affinity binding interactions. The concept of the PROTAC probe was considered as a targeted protein degradation (TPD) probe, and it was introduced to our team in 2024, it could operate according to the catalytic mechanism that required unitary weak interactions with the inducing degradation of the target protein through the ubiquitin–proteasome system (UPS) [2]. Besides, the unique mechanism mentioned above made it realizable for the PROTAC probe to identify and validate elusive targets, which could provide efficient methods for drug discovery. Different from the traditional probe which required sustained high concentrations during the inhibition of target proteins, the PROTAC probe could realize the target degradation by catalytic dose, which was particularly effective for identifying new targets, especially for the low-abundance or untarget proteins. PROTAC probe was successfully utilized in recent studies to elucidate the targets within various natural products and materials with small molecules, such as lathyran diterpenoids, artemisinin derivatives, and evodiamine [3–5]. With the advancement of technology in this field, the development of an advanced PROTAC probe would be crucial for the reveal of the mechanisms during the process of novel compound action and the validation of novel therapeutic targets.

2. Eliminating traditional limitations with nanotechnology

Several challenges occurred in the application of traditional PROTACs, including low water solubility, limited cell permeability, and off-target effects, and the limitations above exhibit a negative effect on the therapeutic efficacy and clinical translation. Recent advancements in nanotechnology provided promising solutions for these problems. For instance, nano-PROTACs could be used to improve the pharmacokinetic properties of PROTAC molecules by encapsulating molecules in nanoparticles which enhanced the in-process stability, solubility, and cellular uptake [6]. Tao et al. demonstrated that encapsulating ARV-771 in GSH-responsive nanoparticles could significantly improve the degradation of BRD4 protein and reduce the expression of downstream oncogene [7]. Additionally, delivery systems based on liposome have been explored to enhance the uptake of PROTACs with specific cell types, such as positive folate receptor cells [8]. Besides, these innovations above could handle the physicochemical limitations of PROTACs, and enable the targeted delivery to cancer cells, thus minimizing toxicity for normal tissues. With the development of nanotechnology, more sophisticated delivery systems could be expected in the future, which could further enhance the therapeutic potential of PROTACs.

3. Expanding target landscapes to conquer undruggable targets

The major limitation for the development of conventional drugs was the inability to target a significant portion of the human proteome, which used to be referred to as “undruggable” targets, including transcription factors (TFs) and RNA-binding proteins (RBPs), which played crucial roles in various diseases, but the defined binding pockets for small-molecule inhibitors lacked. New avenues were opened by the integration of PROTAC technology with oligonucleotides, which could be applied in targeting the traditionally undruggable proteins [9]. For example, TF-PROTACs and RNA-PROTACs were developed to degrade specific TFs and RBPs by leveraging the inherent DNA or RNA-binding domains [10,11]. Additionally, other innovative approaches successfully targeted proteins such as c-Myc, brachyury, and LIN28, indicating the potential of PROTACs to address the therapeutic targets considered to be intractable in the past [12,13]. Significant expansion of the target landscape could be anticipated in the next 5 years, and PROTACs were expected to degrade undruggable proteins with a broader range, thereby providing therapeutic opportunities in the future.

4. Broadening therapeutic indications

Although the focus of current research and clinical trials was on cancer and oncology, the potential applications of PROTAC technology could extend far beyond the indications, as the use of PROTACs in treating viral diseases, neurodegenerative disorders, and metabolic conditions has been explored in recent studies [14,15]. For instance, PROTACs could target viral proteins such as the SARS-CoV-2 main protease, which could indicate its promising antiviral ability in preclinical studies [16]. Additionally, dual-target PROTACs were developed to degrade proteins implicated in neurodegenerative diseases, simultaneously, such as α-synuclein and tau proteins [17]. With the deepening of understanding of PROTAC mechanisms, a broader range of therapeutic applications was expected to be developed in the future, including the treatment of autoimmune diseases, inflammatory symptoms, and even infectious diseases. Additionally, the diversification of indications could significantly improve the clinical relevance and influence of PROTAC technology.

5. Clinical translation and future perspectives

The critical milestone in the development of PROTAC technology will be defined by clinical translation in the next 5 years. Several PROTAC drugs have been in different periods of clinical trials so far, and some of these drugs have shown positive results [18]. For example, ARV-471, which was considered to be estrogen receptor PROTAC, was verged on the completion of clinical trials Phase III, demonstrating significant effect in the treatment of breast cancer [19]. Additionally, KT-333 was defined as a STAT3 degrader, and it showed therapeutic ability in clinical trials Phase I for hematological malignancies [20]. With more clinical trials of PROTACs, the focus of research may transform from improving pharmacokinetic and pharmacodynamic properties to ensuring the safety and efficacy within diverse patients. Simultaneously, the development of biomarkers and companion diagnostics would be essential for the guidance of personalized treatment strategies and monitoring of therapeutic responses. Overall, the successful clinical approval of PROTAC-based therapies could pave the way for the long-term development of TPD, providing effective solutions for diseases that were untreatable in the past.

6. Conclusion

With the persistent advancements anticipated across multiple dimensions, the PROTAC technology was expected to be transformative in the next 5 years. The development of a novel PROTAC probe could enhance the ability to identify and validate new drug targets in the process of catalytic degradation, providing realizable methods that could be alternatives to traditional binding methods with high-affinity. Simultaneously, the combination with nanotechnology could eliminate key limitations of traditional PROTACs technologies by improving stability, cellular uptake, and targeted delivery ability, and the limitations such as poor solubility and off-target effects could be solved. Additionally, PROTACs could provide therapeutic opportunities with the expanding of the target landscape, including TFs and RBPs which were defined as undruggable proteins before. Moreover, therapeutic indications could broaden from oncology to viral diseases, neurodegenerative disorders, and metabolic symptoms, significantly increasing the clinical relevance of PROTACs technologies. Simultaneously, innovative solutions for the expansion of the protein degradation scope have been provided by other novel TPD technology, which was composed of the hydrophobic tag（HyT） based on the UPS system [21], amino acid-based PROTACs (AATacs) [22], autophagy-targeting chimera (AUTAC) based on autophagy degradation [23], autophagosome-tethering compound (ATTEC) [24], alongside the lysosome-targeting chimaeras (LYTACs), based on lysosomal degradation [25]. A new wave of targeted therapies that were was more effective and personalized could be expected with the advancement of technologies toward clinical translation, providing prospects for the treatment of diseases with a wide range. The future of the TPD technology could be represented by PROTAC, which was exceptionally promising and considerable for the potential to profoundly transform the medical field.

Funding Statement

This research was funded by the National Natural Science Foundation of China (No. 82204250); the Hunan Science Fund for Distinguished Young Scholars (No. 2025JJ20098).

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Disclosure statement

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.