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Overcoming the ‘Undruggable’: How PROTACs Are Expanding Therapeutic Frontiers

In recent years, PROteolysis TArgeting Chimeras (PROTACs) have emerged as a transformative approach that leverages the cell’s endogenous protein degradation pathways to selectively eliminate pathogenic proteins. By offering an alternative to conventional inhibition, PROTACs open new avenues for targeting previously “undruggable” proteins and hold great promise for future therapeutic development[1].
In this issue, we will introduce the core principles and mechanisms of PROTACs, highlight recent advances in their molecular design and clinical development, and explore both the opportunities and challenges that lie ahead in this transformative field of targeted protein degradation.
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Cellular Mechanisms of Targeted Protein Degradation (TPD)
Fundamental Principles of PROTACs
Clinical Landscape, Challenges, and Future Directions of PROTACs
Cellular Mechanisms of Targeted Protein Degradation (TPD)
Fundamental Principles of PROTACs
Clinical Landscape, Challenges, and Future Directions of
PROTACs
Cellular Mechanisms of Targeted Protein Degradation (TPD)
Targeted protein degradation (TPD) refers to a broad class of therapeutic approaches that leverage cellular degradation machinery to eliminate specific proteins. This rapidly evolving field includes diverse strategies such as molecular glues, PROTACs, lysosome-targeting chimeras (LYTACs), and antibody-based PROTACs (AbTACs), collectively expanding the therapeutic landscape and offering new avenues to target challenging proteins.
Figure 1. Common TPD technologies[1].
In mammalian cells, protein quality control is primarily governed by two major mechanisms: the ubiquitin–proteasome system and the lysosomal system.
The ubiquitin–proteasome system functions as an efficient recycling center by tagging misfolded or damaged proteins and subsequently degrading them. This process begins with the activation of ubiquitin molecules by the E1 ubiquitin-activating enzyme, which utilizes a small amount of ATP to prepare ubiquitin for action. Ubiquitin is then transferred to the E2 conjugating enzyme and, with the assistance of the E3 ligase, is attached to the target protein destined for degradation. Once the protein is tagged with a polyubiquitin chain, the 26S proteasome recognizes and degrades these marked substrates.
The lysosomal system comprises two main pathways: the endocytic–lysosomal pathway and the autophagic–lysosomal pathway. The endocytic–lysosomal pathway involves the internalization of extracellular materials into vesicles, which are subsequently delivered to lysosomes, where the acidic environment and hydrolytic enzymes degrade the contents. The autophagic-lysosomal pathway, on the other hand, is a cellular self-digestion process in which the cell forms a double-membraned structure known as an autophagosome to sequester cytoplasmic components. The autophagosome then fuses with the lysosome, leading to the degradation of its contents[1-2].
Figure 2. Two main protein quality control machinery in mammalian cells: the ubiquitin–proteasome system and the lysosomal system[1].
Among the expanding repertoire of TPD approaches, PROTACs have emerged as a particularly versatile strategy that leverages the ubiquitin-proteasome system described above. Their unique capacity to catalytically degrade traditionally "undruggable" targets underpins significant clinical potential.
To provide a comprehensive understanding, the following sections will first explore the structural basis and design principles of PROTACs, followed by a comprehensive analysis of their clinical applications, challenges, and future development trends.
Fundamental Principles of PROTACs
Structure and Mechanism of PROTACs
A PROTAC consists of three components: a ligand for the protein of interest (POI), a ligand for an E3 ubiquitin ligase, and a chemical linker connecting them. After entering the cell, the PROTAC brings the E3 ligase into proximity with the POI by forming a ternary complex (POI-linker-E3 ligase). The E3 ligase then mediates the transfer of ubiquitin from the E2 enzyme to the POI, marking it for degradation by the proteasome. Owing to its catalytic nature, a single PROTAC molecule can trigger repeated cycles of POI degradation[3].
Figure 3. Composition and mechanism of action of PROTACs.
Table 1. Comparisons of PROTACs with other therapeutic modalities[3].
Small
molecules		 Monoclonal
antibodies		 siRNA CRISPR PROTACs
Intracelluar target √ × √ √ √
Systemic delivery √ √ × √ √
Tissue penetration √ Poor Poor √ √
Target protein with
scaffolding function		 × √ √ √ √
Eliminates
pathogenic proteins		 × × √ √ √
Oral bioavailability √ × × × √
Ease of developing
high potency/selectivity		 Poor √ √ √ √
Catalytic MOA × × √ √ √
Undruggable targets × √ √ √ √
Optimization Strategies for PROTAC Components
1. Selection of POI and Warhead[4]
The earliest PROTACs entering clinical trials focused on well-established classical targets. These pioneering studies addressed critical questions regarding safety and efficacy in vivo, demonstrating PROTACs' therapeutic potential against solid tumors. However, the most compelling promise of PROTAC technology lies in its capacity to target "undruggable" proteins—offering a paradigm shift from traditional small-molecule inhibition.
So far, there is no widely accepted “gold standard” for selecting PROTAC targets, similar to Lipinski’s “rule of five” for drug-likeness. Generally, an ideal PROTAC target should:
(1) Possess disease-causing gain-of-function changes, such as overexpression, mutation, or mislocalization;
(2) Contain a binding pocket for the PROTAC’s warhead;
(3) Have a surface site that can be ubiquitinated by an E3 ligase;
(4) Preferably include a flexible region that can be processed by the proteasome.
Importantly, high binding affinity or covalent attachment between the warhead and the POI is not required for PROTAC activity. For instance, a study using Foretinib as a warhead showed that the resulting PROTAC only degraded a small subset of kinases targeted by Foretinib, and degradation efficiency was not related to binding strength. Instead, it depended on how effectively the PROTAC formed a ternary complex with the POI and E3 ligase. In fact, very high affinity or covalent binding can hinder PROTAC release from the complex, reducing sustained protein degradation and making the PROTAC behave more like a traditional inhibitor.
Table 2. Reported POIs targeted by PROTACs[5].
Disease fields Targets
Cancer Kinase: BTK, FAK, MEK, IRAK4, BCR-ABL, EGFR, CDK, Aurora A
Transcriptional factors: AR, ER, STAT3, KRAS
Epigenetic proteins: EZH2, BRD, HDAC, KDM5C, SIRT2, EDR5, PRMT5, NSD3, NAMPT, ENL, p300/CBP
Neurodegenerative
diseases		 GSK-3β, LRRK2, α-Synuclein, Tau, TRKA, TRKC, mHTT
Immune disorders HDAC3, H-PGDS, IRAK1, IRAK3, IRAK4
Viral diseases PEGS-2, NS3/4A, Mpro
Others HMGCR, VEGFR2
2. Selection of E3 Ubiquitin Ligase[6]
The choice of E3 ligase can greatly influence the efficiency of targeted protein degradation. For instance, when targeting KRAS(G12C), a PROTAC that recruited CRBN was ineffective, whereas one recruiting VHL successfully degraded endogenous KRAS(G12C). These differences may result from the selection of the warhead, linker, ligase, or factors such as protein size, subcellular localization, and structural compatibility between the ligase and target.
Recent studies reveal that distinct E3 ligases generate divergent degradation profiles—particularly for kinases—governed by three key determinants:
(1) Structural complementarity between ligase and target;
(2) Formation and cooperativity of the ternary complex, which is critical for PROTAC activity;
(3) Subcellular localization and cell-type-specific expression of both ligase and target.
In addition to well-known ligases like CRBN, VHL, MDM2, IAPs, DCAF15, and DCAF16, other “generic” E3 ligases such as RNF4, RNF114, KEAP1, and FEM1B are emerging as promising PROTAC recruiters. Research into their development and in vivo use is ongoing.
Advances in structural biology and AI-based protein structure prediction (e.g., AlphaFold) are also expanding the number of ligases that can be targeted by enabling structure-based ligand discovery.
Tissue- and cell-specific E3 ligases offer opportunities for more selective PROTAC development, especially in tumors where certain ligases are enriched. However, challenges remain, including ensuring druggability, understanding activation mechanisms, and developing effective screening assays. Some ligases are auto-inhibited and require activation, which complicates their application in PROTAC strategies.
In summary, while only a few E3 ligases are currently well-characterized for PROTAC use, ongoing research and new technologies are rapidly expanding the available toolkit, paving the way for more precise and effective protein degradation therapies.
Figure 4. Specialized E3 ligases for potential PROTAC applications[6].
3. Selection of Linkers[7]
Linker length typically ranges from 10 to 20 atoms. Recent analyses show a characteristic L-shaped relationship between normalized degradation activity and linker length. Long linkers diminish degradation potency due to entropic effects, while short linkers cause steric clashes, also leading to a sharp drop in potency. Therefore, PROTAC design often starts with a slightly longer linker, followed by iterative length optimization. Not only is the interaction between the PROTAC molecule and the binding pocket of the target protein affected by the linker length, but the overall physicochemical properties of the PROTAC molecule are also impacted by linker length and structural composition.
Table 3. Different linker motifs and their features[8].
Structures Linker types Key points
Alkyl/PEG ● High synthetic accessibility and commercial availability;
● Enable fine-tuning of linker length;
● Flexible
Rigidifying groups ● Potential potency improvements;
● More favourable physical properities;
● Conformational restriction
Clickable groups ● Facilitates library synthesis;
● High-yielding synthesis;
● Potential H-bond interactions in the TC
CLIPTACs ● Assembled from lower MW precursors;
● More favourable physical properties;
● Compounds must be administered separately to avoid clicking
Photoswitches ● High spatiotemporal control;
● May alleviate toxicity;
● Continuous irradiation may be required if photostates are not bistable
Clinical Landscape, Challenges, and Future Directions of PROTACs
Clinical Development of PROTACs
The therapeutic potential of PROTACs is rapidly translating into the clinic, with multiple candidates currently in clinical trials targeting cancers, autoimmune disorders, and neurodegenerative diseases. Most utilize oral delivery and CRBN-based E3 recruitment.
Table 4. Representative PROTACs in clinical trials[9-10].
Company Degrader Target E3 ligase ROA Highest phase
BeiGene BGB16673 BTK CRBN Oral Phase III
Kintor Pharma GT-20029 AR / / Phase III
Arvinas/Pfizer Vepdegestrant
(ARV-471)		 ER CRBN Oral Phase III
Bristol Myers Squibb BMS-986365
(CC-94676)		 AR CRBN Oral Phase III
Simcere Pharma SIM-0270 ER / Oral Phase III
Arvinas Bavdegalutamide
(ARV-110)		 AR CRBN Oral Phase II
Bristol Myers Squibb BMS-986458 BCL6 CRBN Oral Phase II
C4 Therapeutics CFT1946 BRAF
(V600E)		 CRBN Oral Phase II
Jiangsu HengRui HRS-5041 AR / Oral Phase II
Jiangsu HengRui HRS-1358 ER / Oral Phase II
Prelude Therapeutics PRT3789 SMARCA2 / I.V. Phase II
Ranok Therapeutics RNK-05047 BRD4 / I.V. Phase II
Dialectic Therapeutics DT2216 BCL-XL VHL I.V. Phase II
Hinova HP518 WT/MT AR / Oral Phase II
Arvinas Luxdegalutamide
(ARV-766)		 AR CRBN Oral Phase I
Accutar Biotech AC682 ER CRBN Oral Phase I
Foghorn Therapeutics FHD-609 BRD9 CRBN Oral Phase I
Kymera Zomiradomide
(KT-413)		 IRAK4 CRBN I.V. Phase I
Kymera KT-333 STAT3 VHL Undisclosed Phase I
Sanofi KT-474 IRAK4 CRBN Oral Phase I
Nurix Therapeutics NX-2127 BTK CRBN Oral Phase I
Nurix Therapeutics NX-5948 BTK CRBN Oral Phase I
AbbVie ABBV-101 BTK / Oral Phase I
Accutar AC-176 AR / Oral Phase I
Accutar AC-676 BTK / Oral Phase I
Arvinas ARV-393 BCL6 / Oral Phase I
Astellas ASP-3082 KRAS G12D / I.V. Phase I
Haisco HSK-29116 BTK / Oral Phase I
Haisco HSK-40118 EGFR / Oral Phase I
Kymera KT-253 MDM2, p53 CRBN I.V. Phase I
Kymera KT-621 STAT6 / Oral Phase I
Nurix NX-2127 BTK, IKZF1/3 CRBN Oral Phase I
Nurix NX-5948 BTK CRBN Oral Phase I
Qilu Pharmaceutical QLH12016 / / Oral Phase I
C4 Therapeutics CFT8634 BRD9 CRBN Oral IND-e
C4 Therapeutics CFT8919 EGFRL858R CRBN Oral IND-e
Cullgen CG001419 TRK CRBN Oral IND-e

“/”means undisclosed.

Advantages and Challenges of PROTACs
Table 5. Summary of key advantages and challenges of PROTACs[11].
Advantages
Overcoming drug resistance of cancer For example, ARCC-4 targeting androgen receptor could overcome enzalutamide-resistant prostate cancer and L18I targeting BTK could overcome C481S mutation.
Eliminating both the enzymatic and nonenzymatic functions of kinase FAK has both kinase-dependent enzymatic activity and kinase-independent scaffolding functions, making it difficult for traditional inhibitors to fully block its activity. In 2018, a highly selective FAK PROTAC developed by Craig M. Crews’ group showed significantly greater efficacy than clinical candidate drugs in inhibiting cell migration and invasion.
Degrading the “undruggable”protein targets[12] About 20-25% of known protein targets-including kinases, GPCRs, and ion channels-can be addressed by traditional drug discovery methods. Proteins lacking catalytic activity and/or possessing catalytic-independent functions are still considered “undruggable” targets. STAT3, which is involved in multiple signaling pathways, is an attractive target, but the lack of clear druggable sites on its surface has limited the development of STAT3 inhibitors. In 2019, the STAT3 PROTAC SD-36 was reported to show strong activity both in vitro and in vivo.
Fast and reversible chemical knockdown strategy in vivo Traditional gene knockout techniques such as ZFN, TALEN, and CRISPR-Cas9 are time-consuming, irreversible, and costly, particularly in non-human primates. They are also unsuitable for studying embryonic lethal genes and can result in misleading phenotypes due to gene compensation or off-target effects.

In contrast, PROTACs degrade targets directly at the protein level, enabling functional studies of embryonic lethal proteins in adults. Additionally, PROTACs provide precise temporal control, allowing reversible protein knockdown at specific time points.
Challenges
Expanding the potential of PROTACs for undruggable targets Currently, there are only a few reported examples of PROTACs targeting “undruggable” proteins. More studies are needed to further demonstrate the advantages of PROTACs for these challenging targets.
Differentiating and combining PROTAC and molecular glue mechanisms “Molecular glues” are small-molecule modulators that stabilize protein–protein interactions via E3 ligases. Several small molecules that induce target protein degradation through a molecular glue mechanism have been reported. Recent studies suggest that some PROTACs may degrade target proteins through mechanisms involving molecular glue activity, or even solely by acting as molecular glues. Distinguishing between these mechanisms and exploring how they can be combined represents a key challenge for future research.
Establishing dedicated PK/PD evaluation systems for PROTACs Because PROTACs act through a catalytic mechanism, traditional methods cannot accurately assess their pharmacokinetic (PK) and pharmacodynamic (PD) properties. Therefore, there is an urgent need to establish dedicated PK/PD evaluation systems for PROTAC development.
Identifying PROTAC-compatible target protein ligands Rapid and efficient identification of suitable target protein ligands for PROTACs, especially those targeting protein–protein interactions, remains a major challenge.
Mechanistic gaps impeding rational PROTAC design Limited understanding of the mechanisms underlying PROTAC degradation activity, selectivity, and potential off-target effects-across different targets, cell lines, and animal models-hinders the development of rational design strategies.
Limited E3 ligase diversity Expanding the repertoire of E3 ligases is a critical technical bottleneck in this field.
Challenges——The Hook Effect in PROTACs
PROTAC-mediated ternary complex formation follows a bell-shaped concentration-response curve due to the “hook effect” – at elevated concentrations (1-10 μM), nonproductive binary complexes (PROTAC-POI or PROTAC-E3 ligase) outcompete functional ternary complexes (POI-PROTAC-E3 ligase), reducing degradation efficacy. Recent studies demonstrate that enhancing positive cooperativity in protein-protein interactions (PPIs) can mitigate this phenomenon. The BTK-targeting PROTAC MT-802 exhibited no observable hook effect below 2.5 μM through optimized ternary complex stabilization. Notably, macrocyclization emerged as an innovative strategy to enforce cooperative binding by conformationally constraining PROTACs, energetically favoring productive ternary complexes over binary counterparts. Compared to linear analog MZ1, macrocyclic PROTACs demonstrated superior degradation potency and target selectivity. These insights underscore the importance of ternary complex recognition principles for structure-guided PROTAC design, warranting advanced structural and biophysical studies to unravel the intricate molecular recognition mechanisms underlying this process[13-14].
Figure 5. Dose-dependent degradation of hCAII by Degrader 4 and 5[14].
In concentrations above their maximum activity, both compounds exhibited a well-known attenuation in target degradation known as the “hook effect”.
Summary
PROteolysis TArgeting Chimeras (PROTACs) represent a transformative approach in targeted protein degradation (TPD), leveraging the cell’s own ubiquitin–proteasome system to selectively eliminate disease-associated proteins. Unlike traditional small-molecule inhibitors, PROTACs can degrade both the enzymatic and non-enzymatic functions of protein targets, including those previously considered “undruggable.” The modular design of PROTACs—comprising a ligand for the protein of interest, a ligand for an E3 ubiquitin ligase, and a linker—allows for the catalytic and reversible removal of pathogenic proteins. Recent advances have expanded the repertoire of E3 ligases and linker chemistries, enabling broader therapeutic applications and improved selectivity. Several PROTACs are in clinical development, targeting diverse diseases such as cancer, neurodegeneration, and immune disorders. Despite their promise, challenges remain, including the identification of suitable target ligands, limited diversity of E3 ligases, mechanistic gaps in rational design, and the need for dedicated PK/PD evaluation systems. Additionally, the “hook effect” and the distinction between PROTAC and molecular glue mechanisms require further investigation. Nevertheless, PROTACs offer a powerful platform to overcome drug resistance and expand the therapeutic frontier for previously inaccessible protein targets.
Products and Services Available from MCE
MCE is a globally leading supplier of research chemicals and biochemical reagents, equipped with a strong technical team and state-of-the-art facilities. We have extensive experience in the research, development, and production of PROTAC-related products. Currently, over 3,700 PROTAC-related products are available in our catalog, with the number continually increasing.
For PROTAC research, MCE provides one-stop services, including the design, synthesis, purification, analysis, optimization, and evaluation of PROTAC-related molecules (e.g., ligands for E3 ligases, PROTAC linkers, ligands for target proteins, conjugates, PROTACs, SNIPERs, and PROTAC-linker conjugates for PAC).
For target proteins with unknown ligands, we also offer a wide range of compound libraries and virtual screening resources to facilitate ligand discovery and PROTAC construction. Additionally, we provide comprehensive characterization data—including structure, physicochemical properties, and impurity profiles—for all customized products to ensure quality and consistency.
Figure 6. PROTAC-related products and services offered by MCE.