PROTACs and MGDs: The Revolutionary Modalities for Drug Discovery

Stick, Tag, Destroy: The Science of PROTACs and MGDs – For a long time, traditional drug research focused on inhibitors that block the active sites of disease-related proteins. However, around 80% of these proteins remain “undruggable” because they lack clear binding sites.

Traditional drug discovery has long focused on developing inhibitors that block the function of disease-related proteins by occupying their active sites. However, this approach leaves a significant portion of the human proteome, estimated at approximately 80% of disease-related proteins, as “undruggable” due to their lack of distinct active sites or binding pockets^1,2. Targeted Protein Degradation (TPD) emerges as a revolutionary alternative, employing small molecules to induce the ubiquitination and subsequent degradation of target proteins via the cell’s natural proteasomal or lysosomal pathways². Within the TPD landscape, Proteolysis-Targeting Chimeras (PROTACs) and Molecular Glue Degraders (MGDs) stand out as the leading strategies^1–3.

PROTACs (Proteolysis-Targeting Chimeras)

A PROTAC molecule is typically a heterobifunctional compound composed of three essential parts: a ligand that binds to the protein of interest (POI), a ligand that recruits an E3 ubiquitin ligase, and a chemical linker that connects the two (Figure 1)^4,5.

Figure 1 Structure of a PROTAC. The molecule links an E3 ligase-binding domain to a target protein ligand via a flexible chemical linker, enabling targeted ubiquitination and subsequent proteasomal degradation6.

The core of PROTAC action lies in its ability to bring the POI and an E3 ligase into close proximity, forming a ternary complex^2,3. This induced proximity facilitates the transfer of ubiquitin tags from the E2 conjugating enzyme (which interacts with the E3 ligase) to the POI². Once polyubiquitinated, the POI is recognized and rapidly degraded by the 26S proteasome (Figure 2). A key advantage is that after the target protein is degraded, the PROTAC molecule is released and recycled to target another copy of the POI, enabling sustained degradation even at catalytic drug concentrations^1,2.

Figure 2 PROTAC mechanism of action. The PROTAC bridges a target protein and E3 ligase, triggering ubiquitination and proteasomal degradation1.

Historical Development and Clinical Progress

The concept of PROTACs was first introduced in 1999, with the inaugural peptide-based PROTAC molecule (PROTAC-1) developed in 2001⁷. These early PROTACs validated the principle of targeted protein degradation but were hampered by poor cell permeability, limited oral bioavailability, and proteolytic instability. A significant breakthrough occurred in 2008 with the advent of the first fully small-molecule PROTAC (PROTAC 4), which demonstrated superior cell permeability⁸. This paved the way for identifying small-molecule ligands for key E3 ligases. Cereblon (CRBN) gained prominence in 2010 as the primary target of thalidomide and its analogs. Subsequently, Von-Hippel-Lindau (VHL)-recruiting ligands were discovered in 2012^1–3. CRBN and VHL are now the most widely utilized E3 ligases in PROTAC design due to their favorable drug-like properties.

Figure 3. Key milestones in PROTAC development, from its initial conceptualization and peptide-based molecules to the first small-molecule PROTACs and the emergence of CRBN and VHL as E3 ligase targets2.

Rapid clinical development has followed, with several PROTACs entering clinical trials. Bavdegalutamide (ARV-110), an androgen receptor (AR)-targeting PROTAC, completed Phase II trials for prostate cancer⁹. Vepdegestrant (ARV-471), targeting the estrogen receptor (ER), has progressed to NDA/BLA for ER+/HER2− breast cancer^2,10. NX-2127, a Bruton’s tyrosine kinase (BTK) degrader, has shown efficacy in overcoming drug resistance in B-cell malignancies¹¹. Over 30 heterobifunctional protein degraders are currently under investigation in Phase I-III trials¹. Table 1 summarizes representative clinical-stage PROTACs, their target proteins, the E3 ligases they recruit, and their current clinical phases.

Table 1. Representative clinical-stage PROTACs, their target proteins, the E3 ligases they recruit^1–3.

Molecule	Target Protein	E3 Ligase	Clinical Phase
ARV-471	ER	CRBN	NDA/BLA
ARV-766	AR	CRBN	Phase II
ARV-110	AR	CRBN	Phase II
DT-2216	Bcl-XL	VHL	Phase I/II
NX-2127	BTK	CRBN	Phase I
NX-5948	BTK	CRBN	Phase I
CFT1946	BRAFV600	CRBN	Phase I
KT-474	IRAK4	CRBN	Phase II

Challenges and Optimization

Despite their potential, PROTACs face challenges such as their complex structures and high molecular weight (often >700 Da), which frequently places them outside’s “rule of five”. This can lead to poor cell permeability, metabolic instability, and unfavorable pharmacokinetic (PK) profiles^2,12. To address these, rational design strategies prioritize linker optimization and E3 ligase ligand optimization¹³. Incorporating rigid structures like spirocycles or piperidines into the linker can significantly enhance degradation potency and oral bioavailability². Optimizing E3 ligands involves designing novel scaffolds, such as phenyl glutarimide (PG) derivatives and TX-16, which offer improved stability and affinity compared to traditional thalidomide derivatives^2,4,12,13.

Molecular Glue Degraders (MGDs)

Unlike PROTACs’ bivalent architecture, MGDs are monovalent small molecules. They act by inducing or stabilizing novel protein-protein interactions (PPIs) between an E3 ligase and a target protein (POI). This interaction tags the target protein for degradation via the ubiquitin-proteasome pathway^2,3. MGDs achieve this by modifying the surface characteristics of substrate receptors and E3 ligases, fostering “non-native” interactions that promote ubiquitination and subsequent degradation^3,14. The discovery of MGDs has largely been through serendipitous observation or repurposing existing drug molecules, making their rational design challenging due to the unpredictable nature of these induced interactions¹⁵.

Figure 4. Degradation mechanism of MGD. MGD facilitates the interaction between a protein of interest (POI) and an E3 ligase by binding to either the E3 ligase or the POI, thereby promoting ubiquitination and subsequent proteasomal degradation2.

Advantages and Challenges

MGDs possess several encouraging features. Their monovalent structure results in simpler molecules with lower molecular weights, which more readily adhere to “Lipinski’s rule of five”. This generally leads to better drug-likeness and favorable pharmacokinetic profiles compared to PROTACs². Furthermore, MGDs do not necessarily require a binding pocket on the target protein, expanding the range of “undruggable” proteins they can degrade^1,2. Thalidomide, lenalidomide, and pomalidomide were among the first MGDs discovered and have been approved for treating erythema nodosum, myelodysplastic syndromes, and multiple myeloma, respectively^1,2. Other MGDs, such as CC-90009 (targeting GSPT1) and E7820 (targeting RBM39), are also in clinical development^2,3.

The rational design of MGDs remains a significant challenge. Their mechanisms are inherently unpredictable, and clinical translation faces hurdles such as variable degradation efficiencies across tissues, limited predictive biomarkers, and unanticipated off-target effects. Recent efforts in rational MGD design include strategies like introducing covalent handles to existing inhibitors, effectively converting them into degradation-competent MGDs^1–3,12,15.

Conclusion and Future Outlook

TPD technologies, particularly PROTACs and MGDs, represent a groundbreaking shift in drug development, offering complete elimination of target proteins rather than mere inhibition. This capacity to degrade “undruggable” proteins provides new therapeutic avenues for various diseases, notably cancers. Despite the remarkable progress, challenges remain, including improving metabolic stability, addressing potential off-target effects, and expanding the array of available E3 ligases beyond the currently dominant CRBN and VHL. The integration of advanced computational methods, such as AI-aided drug design, and comprehensive analytical approaches like multi-omics profiling, is anticipated to accelerate the identification of novel degraders and enhance their selectivity and efficacy^2,3. As the field continues to evolve, PROTAC and MGD technologies promise to unlock new therapeutic possibilities for diseases previously considered intractable.

SignalChem Biotech’s Contribution to Targeted Protein Degradation Research

As targeted protein degradation technologies advance, SignalChem Biotech empowers researchers with a robust suite of recombinant E3 ligases—including key molecules like CRBN and VHL—as well as a broad portfolio of target proteins, antibodies, and functional assay reagents. These high-quality, validated proteins and reagents enable the efficient screening, mechanistic interrogation, and optimization of novel PROTACs and molecular glue degraders.

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