Introduction

Proteolysis targeting chimeras (PROTACs) were first reported by Sakamoto et al. in 2001 [1]. PROTACs are heterobifunctional molecules that contain three components: the protein-of-interest (POI) binding moiety, a linker, and E3 ubiquitin ligase binding moiety (Fig. 1a) [2, 88]. However, the similar catalytic domain of the same family members prevented researchers from develo** isoform-specific inhibitors. [89]. To address this problem, the highly specific SGK3-PROTAC1 (Fig. 2d) was developed. This PROTAC was designed by Tovell’s group based on the non-SGK3 selective inhibitor 308-R, to degrade SGK3 specifically [90]. At a low micromolar concentration of SGK3-PROTAC1, intracellular SGK3 levels can be significantly reduced without affecting SGK1 and SGK2. It could be assumed that the selectivity and specificity of SGK3-PROTAC1 derives from the selective recognition of SGK3 by VHL during the formation of ternary complexes induced by SGK3-PROTAC1.

Catalytic mode of action (MOA)

Traditional small-molecule inhibitors act in a dose-dependent manner, to achieve clinical effect by maximizing drug-receptor occupancy. Excessive drug concentrations lead to undesirable side effects and off-target effects [91]. PROTACs can initiate the degradation of target protein catalytic and escape from proteasome [92]. Theoretically, PROTACs can be delivered at lower doses, for longer dosing intervals, and with lower toxicity than small molecule inhibitors since their low concentration is sufficient to degrade proteins and is not constrained by equilibrium occupancy. Because of their catalytic nature, low doses of PROTACs may reduce the probability of off-target effects to occur [77].

Eliminate the accumulation of drug targets

The binding of small-molecule inhibitors to target proteins cansues increased protein accumulation even in a relatively short amount of time [93]. It can be attributed to two reasons: 1). drug binding to target proteins can stabilize the protein structure, thereby extending their half-life, and 2). long-term inhibition will cause upregulation of its compensatory expressio. In general, the accumulation of target protein can be detrimental to the efficacy of drugs. Therefore, for these proteins that are insensitive to inhibitors, it’s extremely suitable to take PROTAC-mediated protein degradation. For example, BRD4, as one of the important bromodomain and extraterminal domain (BET) family members [94]. Researchers demonstrated that targeting BRD4 is an effective means of suppressing MYC-driven cancers [95]. However, the small molecule BRD4 inhibitor, JQ1 (Fig. 2e) and OTX015 resulted in robust protein accumulation, and high concentration of inhibitor is required to suppress downstream c-MYC. In 2015, Lu et al. designed a potent BRD4 PROTAC (ARV-825) by hijacking CRBN E3 ligase, which induced a rapid and sustained degradation of BRD4 protein in all BL cell lines [26]. This highlights the advantages of PROTAC over small-molecule inhibitors.

Others

In addition to the points mentioned above, PROTACs also have other advantages. The occurrence of acquired drug resistance is often closely related to point mutations that can decrease the affinity of the inhibitor to the target protein. PROTACs are able to overcome drug resistance issues via the complete elimination of the target mechanism [96]. Besides, the event-driven model of PROTACs do not require high drug exposure to reduce the risk of off-target effects [97]. Unlike other DNA-level protein knockout techniques, PROTACs enable for the rapid degradation of target proteins in vivo at the post-translational level. In the field of targeted protein degradation (TPD), besides UPS based PROTACs, lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), and antibody-based PROTACs (AbTACs) degrade target proteins through lysomal. PROTACs cannot degrade extracellular and membrane proteins. Therefore, lysosome induced protein degradation can compensate for the lack of PROTACs. LYTACs were first proposed by Banik et al. and consist of a ligand binds lysosome-targeting receptors (LTRs) and a ligand binds extracellular or membrane protein [98]. Currently, only poly-serine-O-mannose-6-phosphonate (M6Pn) and N-acetyl galactosamine (Tri-GalNAC) were LTRs ligands available [99]. The LYTACs have been used to successfully degrade apolipoprotein E4, epidermal growth factor receptor (EGFR), programmed death protein ligand 1 (PD-L1), and CD71 [99]. However, due to the large molecular weight, poor cell permeability, and the possible emergence of immune response in vivo, further studies are needed [100]. In 2019, Takahashi et al. developed AUTACs based on the autophagic process for the degradation of endogenous proteins [101]. AUTACs are a bifunctional molecule with a linker joints POI ligand and autophagic recruitment tag. However, currently published AUTACs are inefficient due to the lack of efficient autophagy pathway recruiters. The autophagic process is extremely complex and may have an impact on natural autophagy, the mechanism of action of AUTACs remain unclear, so it need to be studied in depth [100]. AbTACs utilize bispecific antibodies, with one arm targeting POIs and the other targeting RNF43 E3 ligases [102]. AbTACs can induce POIs internalization and subsequent lysosomal degradation, but the the exact degradation mechanism remains to be confirmed.

The typical application of PROTACs for targeting diverse proteins

In theory, PROTACs can degrade almost all intracellular proteins if there is an appropriate small molecule that specifically binds with those POI, but not all degraders outperform small-molecule inhibitors. Here, we summarize some typical PROTAC molecules that have demonstrated obvious inhibition activities, several of which have advanced to the clinical trial stage.

PROTACs for targeting protein kinases

The human genome encodes over 500 protein kinases [103], making it the largest protein family. Currently, traditional small-molecule inhibitors are the primary treatment options for protein kinases related diseases. A majority of kinase inhibitors focused on the inhibition of receptor tyrosine kinase (RTK) [104]. However, the emergence of drug resistance impaired the clinical benefit, so it is urgent to apply novel therapeutic strategy to overcome this challenge.

In 2013, Crews’s group reported the earliest kinase PROTACs, which was used to target PI3K to block the human epidermal growth factor receptor 3 (ErbB3)–PI3K-Akt (protein kinase B) signal pathway [105]. This PROTAC is composed of two heterospecific peptide sequences recruiting POI and E3 ligase. An ErbB3-derived sequence that can bind to PI3K after it has been phosphorylated. Another sequence derived from hypoxia-inducible factor-1α (HIF1α) can be identified by VHL [105]. The two moieties were conjugated by a PEG linker, and a cell-penetrating sequence was incorporated to improve cell permeability. However, this PROTAC only display moderate potency because of poor permeability and unstable linker [106].

FAK, a tyrosine kinase, regulates many aspects of tumor progression (e.g., invasion, metastasis, and angiogenesis). The leading FAK kinase inhibitor defactinib, failed in clinical trials to treat malignant pleural mesothelioma stem cancer for the lack of efficacy. FAK also has a scaffolding role other than kinase, but kinase inhibitors cannot inhibit kinase-independent function. Cromm et al. designed PROTAC-3 (Fig. 2f) which could effectively induce the degradation of FAK with the IC50 of 6.5 nM [43]. PROTAC-3 is a bifunctional molecule consisting of defactinib and VHL ligand. It effectively inhibits FAK kinase-independent signaling and kinase-dependent signaling by efficient induction of degradation.

Bruton’s tyrosine kinase (BTK) is a member of the non-receptor cytoplasmic tyrosine kinase of the TEC family and a key regulator of the B cell receptor (BCR) signaling pathway, which plays a critical role in the life activities of B-cells like proliferation, survival, and differentiation [107, 108]. BTK is widely expressed in B cell neoplasms, and the clinical interventions are generally performed by inhibiting the kinase activity of BTK [109]. In 2013, FDA approved the first-in-class covalent inhibitor ibrutinib for the treatment of several B-cell malignancies. Ibrutinib binds covalently to Cysteine481 (C481) of BTK with IC50 of 0.5 nM [110, 111]. However, it has been revealed that a cysteine to serine mutation at position 481 of BTK (C481S) is what causes acquired resistance to ibrutinib [112]. So, induction of BTK protein degradation using PROTAC technology has emerged as a promising alternative approach. To date, four BTK degraders have entered clinical trials. They are NX-2127 (NCT04830137) and, NX-5948 (NCT05131022) from Nurix Therapeutics, HSK-29116 (NCT04861779) and BGB-16673 (NCT05006716) small molecule drugs from Haisco and BeiGene respectively. NX-2127 is an oral dual-target small molecule that possesses the activity of BTK degrader and IMiD neosubstrates degrader. A phase I clinical trial of NX-2127 is currently underway for the treatment of relapsed or refractory B-cell malignancies. Preclinical data have demonstrated that NX-2127 could potently induce the degradation of both ibrutinib-sensitive BTKWT (wild type) and ibrutinib-resistant BTKC481S in multiple cancer cell lines and human peripheral blood mononuclear cells (PBMCs) with the DC50 < 5 nM. Additionally, NX-2127 inhibited cell proliferation of BTKC481S in TMD8 cells more effectively than ibrutinib. NX-2127 exhibits immunomodulatory activity through comprised of thalidomide IMiD [113]. Krönke et al. revealed that lenalidomide causes selective ubiquitination and degradation of CRBN neosubstrates Aiolos (IKZF3) and Ikaros (IKZF1) [35]. Lazarian et al. have shown that the overexpression of IKZF3 is a driver of BTK inhibitor resistance in chronic lymphocytic leukemia (CLL) [114]. Therefore, NX-2127 combines BTK degradation with IKZF degradation is expected to enhance its anti-tumor activity. NX-5948 is another BTK degrader designed by Nurix Therapeutics. Unlike NX-2127, NX-5948 lacks immunomodulatory activity and has the ability to cross the blood brain barrier (BBB) in animal models. NX-5948 displayed similar performance that preclinical data have shown that NX-5948 induced the degradation of BTK (50% degradation efficiency at < 1 n M) in lymphoma cell lines and PBMCs [115].

PROTACs for targeting nuclear receptors

Nuclear receptors (NRs) belong to the family of transcription factors. Unlike other traditional transcription factors, its main function is to convert external the signal to transcriptional output [21]. A typical NR includes three domains: two structural domains that bind DNA and ligand respectively, and an unstructured N-terminal regulatory domain that is highly variable in terms of both sequence and size [116]. Ligand agonist binding confers a conformational change that results in exposure of the nuclear localization signal (NLS), which allows NR to translocate to the nucleus and bind the response elements. Small-molecule inhibitors that bind to ligand binding domain have been designed to activate or block the signal transduction function of nuclear receptors. However, small-molecule inhibitors have several disadvantages. For instance, our understanding of the concept of pure inhibitors is not clear, as continual AR antagonists prove to be agonists when the AR gene is overexpressed or mutated [117, 118]. In addition, some ligands for orphan NRs have not yet been identified, thus making it more complicated to target NRs to treat diseases. The advent of PROTAC technology has made it possible to target a wider range of NRs. NRs such as AR and ER participate in various important physiological progress in the body, and are closely related to prostate cancer and breast cancer. Therefore, a series of PROTACs targeting ER or AR have been developed.

AR signaling is critical in the development and maintenance of the normal function of prostate. AR not only plays a key role in the maintenance of musculoskeletal and male sex-related functions but also in the progression of prostate cancer [119]. Inhibition of AR function with AR antagonists such as enzalutamide and apalutamide is a common strategy in the treatment of prostate cancer [120]. Unfortunately, castration-resistant eventually occurs in patients with antiandrogen therapy [121]. PROTACs emerged as an alternative potential therapeutic approach to compensate for the shortcomings of AR inhibitors. Salami et al. synthesized a potent AR PROTAC ARCC-4 (Fig. 2g), which comprised of enzalutamide derivative and E3 ligand recruiting VHL. Compared with its parent inhibitor enzalutamide, ARCC-4 can effectively degrade AR and AR mutants caused by long-term use of clinical inhibitors, without leading to the presence of drug resistance [118]. It is well-known that ARV-110 (Fig. 2g) is the first AR-targeting PROTAC in clinical trial. The latest clinical trial data indicated that ARV-110 has an acceptable safety profile. The maximum tolerated dose (MTD) has not been established and the determination of the recommended phase 2 dose (RP2D) continues. In addition, ARV-110 has demonstrated antitumor activity in patients with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamid and/or abiraterone administration [44]. Recently, Wang’s group reporteded two highly potent and orally bioavailable AR PROTACs, ARD-2128 and ARD-2585 (Fig. 2g). ARD-2128 features an optimized AR antagonist linked to thalidomide via a rigid linker, achieving 67% oral bioavailability and better antitumor activity than enzalutamide in mice [151]. Here we introduced a specific and potent STAT3 PROTACs. Bai et al. reported the first STAT3 PROTAC SD-36 (Fig. 2i) that not only could effectively and specifically degraded STAT3 and has the antiproliferative activity of leukemia and lymphoma cell lines [147]. SD-36 consists of a selective STAT3 inhibitor SI-109 and lenalidomide and is a typical successful example of how PROTACs can be applied to target challenging proteins such as transcription factors.

Design and development of PROTACs

The degradation activity of PROTACs not only depends on the affinity of both ends to their respective target, but also relies on the formation of ternary complex that can form stable PPI. Currently, the construction of PROTACs largely relies on empirical analyses and structure–activity relationship (SAR) studies. However, synthetic difficulty presents significant limitations for rapid synthesis of a wealth of PROTAC compound libraries. By analyzing and summarizing published PROTACs structures, we will provide conventional strategies in PROTAC design to accelerate PROTACs discovery. In addition, we have listed some recently reported PROTACs that recruit traditional E3 ligases with corresponding degradation activity (Table 4).

Table 4 Representative compounds of PROTACs reported since 2019
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E3 ligase and its ligand

Of the more than 600 ligases identified, only a few with small molecule ligands have been used for PROTAC targeting [163]. We list the commonly used E3 ligases and their ligands (Fig. 3). Cao et al. summarized and analyzed the structures of highly active PROTACs published over 20 years, and they found that CRBN, VHL, and cIAP ligands were used most frequently, of which CRBN accounted for 60.1%, VHL for 30.1%, and cIAP for 5.5% [164]. The main reason is that CRBN is widely expressed in tissues with high abundance and CRBN-based PROTACs have better degradation efficiency. In addition, CRBN ligands have better drug-like properties compared to the VHL ligand. PROTACs recruiting MDM2 and cIAP usually have high molecular weight and poor tissue permeability, indicating that the oral bioavailability may be a potential concern. Some other E3 ligases such as DCAF11 [27], DCAF15 [28], DCAF16 [29], KEAP1 [30], and RNF114 [31] etc., are less used for the following reasons: their ligands are derived from natural products with poor affinity, and are difficult to synthesize, and most of these E3 ligases are recruited by irreversible PROTACs, which have poor degradation activity and some potential toxicity. Of note, different recruited E3 ligases have been shown to induce different degrees of protein degradation [165]. The major reasons are as follow: different expression levels of E3 ligases in different cells may contribute to the different degradation efficiency. And some proteins have different degrees of selectivity for different E3 ligases. Therefore, in the process of designing the PROTACs, ligands targeting CRBN or VHL should be preferentially chosen, as these two E3 ligases have the widest range of applications. As an illustrative example, both ARV-110 and ARV-471 selected CRBN ligase as the E3 ligand. Here, we review the traditional E3 ligases and their ligands used in PROTAC design.

Fig. 3
figure 3

Representative small molecule ligands of E3 ligases used for PROTACs. Blue dots indicate the appropriate linker attachment site

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Linker design strategies of PROTACs

Type of linkers

Maple’s group built a database containing more than 400 published PROTACs to find a general principle that has been applied in PROTAC [166]. A summary of the linker structures in the database (Table 5) reveals that the frequently used linkers in PROTACs design are PEG and (un)saturated alkane chains with varying lengths up to now [81]. Due to the facile chemical synthesis feature, alkyl linkers are often used for the synthesis of PROTAC molecules to identify the optimal linker length. However, introduction of alkyl linkers might reduce the cell permeability of PROTACs due to their high hydrophobicity. Alkyl chains containing heteroatoms (oxygen atoms or nitrogen atoms) have improved hydrophilicity over alkyl chains alone. In addition, incorporating PEG chain can enhance the solubility and uptake of PROTACs by cells. More than half of the published PROTACs structure contained alkyl and PEG motifs. Alkyl, PEG, and glycol chains are incorporated into the PROTACs to increase the flexibility. However, their introduction can affect the pharmacokinetics (PK) properties of PROTACs. In recent years, linear linkers are gradually replaced by rigid linkers, such as alkynes and saturated heterocycles (piperazine and piperidine). The incorporation of aromatic rings or alkyne chains imparts some rigidity and promotes stable ternary complex formation. It also facilitates the solubility and cell permeability of PROTAC [206], suggesting that targeting PGES-2 may be a potential approach for INM-based antiviral PROTACs design. Desantis et al. designed four INM-based PROTACs, but the biological evaluation results showed that only two compounds were about 4.5-fold more potent than INM, as well as a wide-spectrum antiviral activity against the β-coronavirus HCoV-OC43 and α-coronavirus HCoV-229E [201].

Other PROTACs

In 2020, Rao et al. reported the first PROTAC of HMG-CoA reductase (HMGCR), which is the rate-limiting enzyme in the cholesterol biosynthetic pathway [207, 208]. They synthesized a series of PROTACs by tethering Atorvastatin and CRBN ligands. After optimization and screening, they ultimately found the most potent degrader P22A (Fig. 2m) with DC50 of 0.1 μM [209]. This PROTAC stressed the potential application for the treatment of hypercholesterolemia and cardiovascular disease. In addition, PROTACs are a promising therapeutic approach in other non-oncoproteins. Li et al. reported the first PROTAC that induced degradation of α1A-adrenergic receptor (α1A-AR) and is also the first PROTAC for G protein-coupled receptors (GPCRs) [210]. They connected α1A-AR inhibitor prazosin with pomalidomide by different linkers and finally found the potent compound 9c (Fig. 2m). 9c could inhibit the proliferation of PC-3 cells and cause tumor growth slowdown, which provided a new strategy for the treatment of prostate cancer. Hu et al. presented the first PROTAC of indoleamine 2,3-dioxygenase 1 (IDO1) [65]. IDO1 has been extensively reported as key immune checkpoint, which overexpressed in multiple cancers [211]. Hu et al. discovered the first PROTAC 2c (Fig. 2m) which induced the pronounced and sustained degradation of IDO1. Si et al. showed that PROTAC of hematopoietic progenitor kinase1 (HPK1) helped to improve CAR-T cell-based immunotherapy [212]. PROTAC technology is so widespread in the field of disease treatment, making it a powerful tool for drug discovery.

Disadvantages and future challenges of PROTAC

As an emerging technology, PROTAC has attracted great attention from academia and the pharmaceutical industry. The development of any new technology comes with various opportunities and challenges, and PROTAC is no exception. The prospect of potential opportunities and challenges for PROTAC will contribute to the research and development of targeted protein-degrading drugs. Although PROTAC has unique advantages over other drug discovery paradigm, it also has some disadvantages, which bring nonnegligible issues and challenges:

  • Pharmaceutical property: PROTAC molecule is more complex than traditional small-molecule drugs and has more potential metabolic sites, which affects the metabolic stability of PROTAC molecules. At the same time, traditional small-molecule inhibitors generally follow the “Rule of Five”, but most of the reported PROTACs tend to have a molecular weight greater than 700, resulting in poor permeability, low solubility and unsatisfactory oral bioavailability [213]. Therefore, how to improve physicochemical properties of PROTAC molecule will be the key to its successful drug formation if “the Rule of Five” are not satisfied.

  • Resistance: First, PROTACs can cause drug resistance through the change in the genome of the core component of the E3 ligase complex. Significantly reduced expression of CRBN gene or CUL2 gene can also cause resistance to PROTACs [214, 215]. Studies have shown that deletion of the CRBN genome is the main reason for myeloma cells to develop resistance to IMiDs. Secondly, the action of PROTAC depends on specific E3 ligase subtype, and the expression of specific E3 ligase limits the application of PROTAC in different cell types. Although the human genome encodes hundreds of E3 ubiquitin ligases, only a few E3 ligases and small molecule ligands have been used for PROTACs. Therefore, finding more kinds of E3 ligases for the research and development of PROTAC drugs might be the way to solve drug resistance [216].

  • “Hook effect” and “Off target”: How to avoid Hook effect and off-target effect is also a major challenge for PROTAC drugs development. The higher the concentration of drugs, the better degradation effect is not necessarily for PROTACs, which is often referred to as the “Hook effect”. In the research of PROTACs, it has been found that significantly higher concentration than DC50 will result in self-inhibition effect to compensate degradation efficiency, called “Hook effect” [217, 218]. In addition, the mechanism of off-target effects of PROTACs molecules have not been fully understood [219]. PROTACs can completely degrade target protein, thus inhibit all functions of target protein. However, in this process, normal protein may be accidentally injured, off-target effect and toxicity are also one of the biggest challenges. For example, studies have shown that thalidomide derivatives can cause degradation of transcription factors such as IKZF1, IKZF3 and GSTP1 [214]. Further studies found that the degradation of thalidomide derivatives on transcription factors such as GSPT1 was due to their “molecular glue” effect.

  • Target selection: To date, what targets are appropriate for PROTAC technology to achieve better benefits than small-molecule inhibitors are not fully understood and most of the target proteins of the PROTACs are part of the “druggable” protein. In fact, one of the greatest advantages of PROTAC technology is its potential to handle “undruggable” target. Because PROTAC technology only needs temporarily mediate the formation of ternary complexes, low affinity POI ligands can be incorporated into PROTAC molecules. Unfortunately, there are only few PROTAC molecules targeting “undruggable” proteins to date. Therefore, another challenge for PROTACs is the need to develop more molecules that target “undruggable” proteins and thus embody the advantages of PROTAC technology.

Discussion and conclusion

As an emerging paradigm for drug discovery, PROTACs have attracted great attention from academia and industry. Although PROTAC technology has many advantages in drug development, there are still many obstacles and challenges in the process of discovery and clinical application, such as off-target, cell permeability, stability, and large molecular weight, etc. In addition, the issues of oral bioavailability and drug integrity are also ongoing challenges for PROTAC drug development. It is worth noting that PROTAC still has many advantages in clinical application compared with other traditional small-molecule inhibitors. First, PROTAC plays a role by inducing the degradation of pathogenic proteins, so it can promote the degradation of multiple rounds of target proteins, assisting to eliminate off-target effects and accumulation of drug targets. PROTAC can also degrade some proteins that are considered “undruggable”, such as transcription factors. Secondly, PROTAC has the advantages of improving selectivity and specificity, overcoming drug resistance. In short, the current status of PROTAC drug development is the coexistence of both advantages and disadvantages, but how to solve these problems will be the key to the success of PROTAC drug development.

The discovery of efficient PROTAC molecules is a time-consuming and challenging process, such as the optimization of linker length and structure. It is urgent to summarize a general method for designing efficient PROTAC molecules. At present, the design and optimization of PROTAC mainly focus on the structure–activity relationships research of POI ligands and linker. Among them, linker is not only critical to the degradation activity of PROTACs, but also greatly affects the membrane permeability, metabolic stability and drug availability. Therefore, how to effectively design and link POI and E3 ligands is the key to the molecular design of PROTACs. Up to now, the principles guiding the design of linker, including length and composition, have not been fully understood. On the other hand, photo-PROTAC designed based on “photo control linkers” also has some advantages over traditional drugs, which is also introduced in this article. It is expected that the newly emerging photo-PRTOAC can become a leading way among PROTAC drugs. In this review, we summarized the general principles in the design of PROTAC, providing a systematic understanding for the research and design of PROTACs. In addition, E3 ligase is also crucial in the composition of the ternary complex. However, among the hundreds of E3 ligases encoded by the human genome, only a few E3 ligases are used in PROTACs, and the progress in discovering new E3 ligases and their ligands is far behind the research of PROTACs. So far, the majority of PROTACs induce target protein degradation by recruiting E3 ligases CRBN, VHL, MDM2 and IAP, and the research on PROTACs by only these E3 ligases is still far from enough. Therefore, it is necessary to explore more novel E3 ligases to accelerate the development of PROTACs. However, it can be predicted that the number of E3 ligands may increase significantly in the future, which will provide more options for the design of PROTACs.

PROTAC technology has been developed for nearly 20 years, and some molecules have entered clinical trials, which reveals the huge therapeutic potential of PROTACs in tumor, immune disease, neurodegenerative disease, cardiovascular disease and viral infection. There are also studies around the world using this technology to treat COVID-19. So far, two PROTAC drugs ARV-110 and ARV-471 have entered the phase II clinical trial, which are used to treat prostate cancer and breast cancer respectively. Although more than ten drugs are in clinical trials, clinical research data are still insufficient, and more clinical studies are needed to prove the prospects of PROTAC technology. With the deepening of research, these obstacles will be basically solved in the near future. Once more drugs enter the clinical application, it will open a new era of drug research and development.

Although there are still many obstacles and challenges to be overcame, PROTACs have great therapeutic potential with its unique advantages. It is believed that in the future, with the development of technology and in-depth research, the design and synthesis of PROTACs will be gradually optimized, which will eventually open up a broad road for the treatment of various diseases, and is expected to provide clinical therapeutic benefits in the near future. In a word, PROTAC technology not only provides a powerful tool for the research in the field of pharmaceutical chemistry, but also brings great hope for the development of clinical drugs in the future.