New approaches in drug discovery currently focus on the concept of a „magic bullet“ molecule. One that precisely targets an intended pharmacological role without off-target actions or unwanted side-effects. Traditional small molecule drugs and many biologics work by binding a protein and inhibiting protein activity. But what if it were possible to selectively remove a protein of interest, even within a specific tissue or cell type. Recent technological advancements in targeted protein degradation (TPD) leverage the cell‘s natural protein management systems to achieve this. There has been particularly exciting progress in this area that worth highlighting. First I will provide some background on this field, followed by new developments, and their potential implications. Finally, I will be reviewing several companies that are developing interesting therapeutics using Targeted Protein Degradation (TPD). I will also spotlight some of the molecules in their pipelines.
Mechanisms of Targeted Protein Degradation
Many TPD methods utilize key features of the cell’s ubiquitin-proteasome system (UPS). The core of the UPS is the ubiquitin conjugation system, comprising three main components: E1, E2, and E3 (Zhao et al., 2022). The E1 activates ubiquitin using ATP and transfers it to E2, a ubiquitin-conjugating enzyme. E2 then partners with an E3 ubiquitin ligase to transfer the ubiquitin to a lysine residue in a target protein. Proteins destined for degradation are often modified with multiple ubiquitin units, which directs them to the cell’s 26S proteasome for breakdown (Chirnomas et al., 2023). The system‘s flexibility stems from the diverse array of over 600 known E3 ligases in the human genome, which can be single proteins or multi-protein complexes. The substrate specificity for degradation is mostly determined by the specific binding properties of the E3 (Békés et al., 2022, Liu et al., 2023).
Subsequent to UPS-based TPD, additional methods have emerged that leverage lysosomal and lysosome-autophagosome degradation pathways. Lysosomes, as the primary cellular degradation compartment, degrade proteins and organelles through endocytosis, phagocytosis and autophagy. Unlike UPS-based methods, which typically target soluble intracellular proteins, lysosome-based TPD can potentially remove aggregated, membrane-bound, or extracellular protein targets as well (Zhao et al., 2022). A summary of lysosome-dependent protein degradation strategies is shown in Figure 3.
PROTAC the Original Engineered TPD
Proteolysis targeting chimeras (PROTAC) are a prominent and relatively well developed group of TPD molecules. PROTACs are heterobifunctional molecules designed to simultaneously bind an E3 ligase and a target protein of interest (POI). This close proximity facilitates target ubiquitination, leading to subsequent degradation by the proteasome. The first PROTAC molecule was engineered nearly 25 years ago, and the technique has seen significant expansion since then (Zhao et al., 2022). Initially, PROTACs were designed to recruit target proteins to the Cullin-RING ligase (CRL) E3 complex known as SKP1-CUL1-F-box (SCF) for ubiquitination and degradation (Tsai et al., 2025). The field of E3 ligases targeted by PROTACs has since expanded to include substrate recognition by HDM2 (aka MDM2), members of the inhibitor of apoptosis (IAP) family, cereblon (CRBN), and von Hippel-Lindau (VHL) (Tsai et al., 2025). Among the over 200 CRL possibilities, CRL4CRBN and CRL2VHL are the two most prevalent E3s targeted so far (Gregory et al., 2024). A timeline for TPD and therapeutic advancements is shown in Figure 1 and Figure 2.
A PROTAC is engineered by linking an E3 binding ligand to a molecule that binds a POI via a flexible linker. This design allows for rational and specific development of numerous PROTACs. In a therapeutic context, there are tenets for choosing a degrader target to take advantage of TPD‘s unique features and complement traditional therapeutics. These include:
- Classically undraggable targets
- Potential for resistant mutations
- Gene/protein overexpression
- Existence of differential isoform effects
- A focus on scaffolding proteins
- A focus on protein with aggregation potentials.
Additionally, emerging medicinal chemistry guidelines for designing effective degraders involve sophisticated tuning of the linker domain’s size and flexibility (Chirnomas et al., 2023). One drawback of PROTACS is that the combination of two binding domains and a linker can result in relatively large molecules, which may hinder pharmacological use (Zhao et al., 2022).
Figure 1: Timeline for TPD and therapeutic advancements (Source: Gregory et al., 2024)
Figure 2: Development history of PROTAC (Source: Békés et al., 2022)
Molecular Glues, the Minimalist Approach to TPD
Molecular glue degraders (MGD) operate similarly to PROTACs by directing target proteins to the proteasome via the ubiquitin-proteasome system (UPS). The term „molecular glues“ originated from research on the mechanism of immunosuppressive agents like cyclosporine A and FK506 (Zhao et al., 2022). MGD molecules differ from PROTACs in that they enhance the protein-protein interaction between an E3 ligase and a POI without directly binding to both in a ternary complex (Jochem et al., 2025, Tsai et al., 2025). Most known MGD bind to an E3 ligase (fewer bind to the target protein) and induce or stabilize a conformation that promotes E3-target association.
Another key difference is that MGD are generally much smaller molecules than PROTACs. Many MGD molecules belong to the immunomodulatory imide (IMiD) class, whose core members are thalidomide, lenalidomide, and pomalidomide (Békés et al., 2022 [Figure 2], Zhao et al., 2022). These molecules were discovered to be MGDs many years after their initial description. This is exemplified by the decades between the discovery of thalidomide and the elucidation of its mechanism of action. Though thalidomide was first used clinically in the 1950s, it wasn‘t until 2010 that it was found to bind to CRBN. Shortly thereafter, it was found that lenalidomide and thalidomide, used to treat multiple myeloma, exerted their effects by acting as MGD targeting transcription factors IKZF1 and IKZF2 (Tsai et al., 2025). Specifically, thalidomide derivatives reshape the binding surface of CRBN, allowing it to bind beta-hairpin structures present in zinc-finger domains. Later, the aryl-sulfonamide indisulam was identified as an MGD targeting the splicing factor RBM39. Since most MGDs have been found fortuitously and retroactively, these molecules are currently challenging to design for specific purposes. However, due to their generally small size, they are intrinsically well-suited as potential drugs. Their relatively small size has also led to MGDs being used as the basis for designing heterobifunctional PROTACs, starting with the MGD core structure, thus somewhat blurring the distinctions between the categories.
Lysosome-Mediated Targeted Protein Degradation
There are various TPD methodologies that utilize lysosomes to degrade POI within the cell. One such technology, similar to PROTACs, is the Lysosome-Targeting Chimeras (LYTAC). These engineered molecules are designed to simultaneously bind to a target protein and a lysosome-targeting receptor (LTR) on the cell surface (Zhao et al., 2022). This binding facilitates the internalization of extracellular or membrane-bound proteins via endocytosis, leading to their degradation within the lysosome. Another approach is Antibody-based PROTAC (AbTAC), which employs a bispecific antibody that targets both the POI and a transmembrane E3 ligase (e.g., Ring Finger protein 43 (RNF 43)). This also leads to protein internalization and degradation through the endosome-lysosome pathway. An interesting variation of LYTAC replaces the engineered protein with a DNA aptamer that simultaneously binds POI and an LTR (Zhao et al., 2022). This bispecific aptamer chimera offers unique flexibility due to the rapid modifiability of DNA molecules and their distinct immunological properties. Furthermore, the GlueTAC method is another relative of LYTAC, where an engineered molecule features a POI-targeting nanobody conjugated to a cell-penetrating peptide and lysosomal sorting sequence (CPP-LSS) (Zhao et al., 2022). All these lysosome-dependent methodologies offer the advantage of potentially directing the degradation of extracellular or membrane proteins. This capability could be crucial for developing treatments for neurological disorders such as Alzheimer’s disease (AD).
Targeted Protein Degradation via Autophagy-Lysosome Pathways
In addition to the lysosomal degradation routes there are TPD technologies that leverage the autophagy-lysosome degradation route. One such technology is the autophagy-targeting chimera (AUTAC). As described by Zhao et al. (2022), AUTACs utilize an autophagy recruitment signal, such as 8-nitrocylic guanosine monophosphate, linked to a POI targeting ligand, This triggers a specific form of polyubiquitination on the POI, directing it to the lysosome for degradation. Another approach is the autophagosome tethering compound (ATTEC). ATTEC molecules simultaneously bind to both the POI and the LC3 (aka microtubule-associated protein 1 light chain 3, a member of the highly conserved ATG8 family) protein. Since LC3 is a critical component of the autophagosome, this linkage facilitates POI degradation via the autophagosome-lysosome pathway. A further variation is the AUTOphagy-Targeting Chimera (AUTOTAC). AUTOTACs consist of a POI-targeting warhead linked to a molecule that interacts with p62/SQSTM1. In this mechanism, p62, an LC3 interacting molecule, directs the POI towards autophagy-lysosome degradation. While lysosomal and autophagosomal degradation technologies are generally less mature than PROTAC or MGDs, they offer distinct features that could be valuable in a pharmacological context.
Unambiguous Target Identification in TPD Using DegMS
Earlier this year, a quite ingenious methodology, called DegMS, was developed to enable large-scale, rapid screening for identifying the direct protein targets of small molecule degraders (Jochem et al., 2025). This technology addresses a significant bottleneck in development of small molecule degraders by quickly and unambiguously determining their POI targets and other affected proteins. Deg MS ingeniously combines click chemistry (using azidohomoalanine (AHA), a clickable methane analog), stable isotope labeling by amino acids in cell culture (SILAC), and mass spectrometry (MS) for protein detection and quantification.
The process begins with culturing cells under SILAC-intermediate labeling conditions. Cells are then exposed to AHA and either a SILAC-light or SILAC-heavy amino acid condition for an 8 hour pulse labeling period. This creates a pool of uniquely isotopically labeled proteins (heavy or light) across the cellular proteome. Both heavy and light pools incorporate AHA, enabling selective activity and enrichment using click chemistry. Following pulse labelling, cells are switched back to SILAC-intermediate media. Simultaneously, SILAC-heavy cells are exposed to a protein degrader, while SILAC-light cells receive a control treatment. After degrader exposure, AHA-containing proteins are enriched through click chemistry, then identified and quantified by MS. This protocol ensures that proteins synthesized after degrader treatment do not contain AHA and are therefore not captured during the enrichment. Additionally, newly synthesized proteins after drug treatment are differentially isotopically labeled (intermediate) making them distinguishable by MS from SILAC-heavy or SILAC-light proteins in the experimental and control pools, respectively. This exclusion of secondary effects on transcription or translation increases confidence in attributing observed differences to direct degradation effects (Jochem et al., 2025).
Using this technique, Jochem et al., (2025) successfully identified the direct TPD targets of the small molecule degrader dCeMM2 as cyclin K, CDK12 and CDK13. This finding is entirely consistent with dCeMM2 action as a MGD specific for cyclin K. The authors further characterized the molecular targets of two additional IMiD family degraders, including one whose targets were previously unknown. This new technique thus represents a powerful tool for degrader substrate discovery in TPD.
Figure 3: Summary of lysosome-dependent protein degradation strategies (Source: Zhao et al., 2022).
Targeted Protein Degradation in Cancer Therapy
The bulk of early efforts to develop drugs utilizing TPD are focusing on their application in cancer treatment. As of January 2023, at least 18 protein degraders were in clinical trials for various cancers, a number that has likely grown (Chirnomas et al., 2023). Early efforts have concentrated on key cancer-driving proteins. For instance, the androgen receptor (AR) in prostate cancer is a major target (Chirnomas et al., 2023). Similarly, targeting the estrogen receptor (ER) is a significant area of focus for TPD in ER-positive breast cancer, which constitutes the majority of breast cancer cases in women (Chirnomas et al., 2023). Some existing breast cancer drugs, such as fulvestrant and elacestrant, are classified as selective estrogen receptor degraders or downregulators (SERD). However, these do not necessarily initiate protein degradation via E3 ligase association, as seen with PROTACs. Rather, most SERDs appear to indirectly cause proteasomal degradation of ER by altering its subcellular location, moving it away from the nucleus. Another important target for PROTAC development is Bruton’s tyrosine kinase (BTK). As a signaling kinase, BTK is crucial for B cell development. Mutations in BTK, through their role in B cell survival and proliferation, can drive B cell malignancies such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Finally, bromodomain-containing protein 9 (BRD9), a component of the BAF (Brahma-associated factor) chromatin remodeling complex, is also the target of several anti-cancer protein degraders in early clinical trials.
The Future Potential for TPD in Neuroscience
With the advance of TPD technology the potential therapeutic targets have expanded from cancer into the neurosciences (Gregory et al., 2024). The first PROTAC degrader for a neurological indication, ARV-102, entered clinical trials in 2024 for Parkinson’s Disease (PD) and progressive supranuclear palsy (PSP). TPD offers a logical therapeutic route for many neurodegenerative disorders such as Alzheimer’s Disease (AD), PD, PSP and amyotrophic lateral sclerosis (ALS), as these are all proteinopathies. Well-known examples include Tau protein involvement in AD and PSP, and alpha-syneuclein in PD. Tau and alpha-synuclein are intrinsically disordered proteins (IDP) prone to irreversible aggregation (Gregory et al., 2024). These two IDPs also lack conventional enzymatic activities that can be targeted by pharmacological inhibitors, suggesting that a non-classical approach like TPD could be highly effective. Other strategies aimed at lowering protein levels such as antisense oligonucleotides (ASO) and siRNA, have already demonstrated success in preclinical models for AD, PD, and ALS (Gregory et al., 2024). Some caution is warranted, as many PROTACs used in research settings have unknown bioavailability, particularly via oral administration, and unknown penetration of the blood-brain barrier (BBB), which could limit their clinical utility. Nevertheless, advances in small molecule MGD technology could potentially solve these challenges (Békés et al., 2022, Gregory et al., 2024).
Companies with TPD Degrader Molecules in Development
Arvinas: A leader in TPD development, headquartered in New Haven, CT, founded in 2013, and publicly traded on NASDAQ (ARVN). They are developing novel therapeutics to treat cancer, pro-inflammatory, autoimmune. and rare diseases. Key pipeline assets include:
- Vepdegestrant: An oral PROTAC targeting the estrogen receptor (ER) for breast cancer, currently in Phase 3 trials. Developed in collaboration with Pfizer.
- ARV-102: An oral, blood-brain barrier (BBB) penetrant PROTAC designed to degrade leucine-rich repeat kinase 2 (LRRK2) for neurological diseases including PD and PSP.
Kymera: A clinical-stage biotechnology company specializing in TPD, founded in 2017, headquartered in Cambridge, MA, and publicly traded on NASDAQ (KYMR). Key pipeline assets include:
- KT-621: An oral degrader of Signal Transducer and Activator of Transcription 6 (STAT6) in Phase 1 trial, intended for Chronic Obstructive Pulmonary Disease, Asthma, Atopic Dermatitis, and related immune/allergic disease. STAT6 is a central driver of Th2 inflammation.
- KT-579: A degrader targeting Interferon Regulatory Factor 5 (IRF5), an undrugged transcription factor involved in innate and adaptive immune response, with potential for Lupus, Sjögren’s Syndrome, Rheumatoid Arthritis and other indications.
C4 Therapeutics: A clinical-stage biotechnology company developing TPD medicines, founded in 2015, headquartered in Cambridge, MA, and is publicly traded on NASDAQ (CCCC). They focus on early-stage therapies. Key pipeline assets include:
- Cemsidomide: An orally bioavailable small-molecule degrader of IKZF1/3. IKZF1/3 are transcription factors that drive multiple myeloma (MM) and non-Hodgkin’s lymphomas (NHL).
- CFT8919: A degrader targeting EGFR containing an oncogenic L858R mutation to treat non-small cell lung cancers.
- CFT1946: A degrader targeting mutant BRAF V600 intended to treat solid tumors.
Nurix Therapeutics: A biopharmaceutical company with extensive TPD pipeline, founded in 2012, headquartered in San Francisco, CA, and publicly traded on NASDAQ (NRIX). They leverage their expertise in E3 ligases and the proprietary DNA-encoded library (DEL)-AI discovery engine. Key pipeline assets include:
- Bexobrutideg (NX-5948): An oral, CNS-penetrant, small molecule degrader of Bruton’s tyrosine kinase (BTK) for chronic lymphocytic leukemia (CLL), NHL, and Waldenström macroglobulinemia (WM).
- NX-1607: A small molecule inhibitor of Casitas B-lineage lymphoma proto-oncogene-b (CBL-B), a critical immune regulator that can contribute to immunosuppression in the tumor microenvironment..
Olema Oncology: A preclinical biotechnology company developing new drugs for the treatment and prevention of estrogen receptor (ER) positive breast cancer. Founded in 2017, headquartered in San Francisco, CA, and publicly traded on NASDAQ (OMLA). Key pipeline assets include:
- Palazestrant: An oral Complete Estrogen Receptor Antagonist (CERAN) and Selective Estrogen Receptor Degrader (SERD). Phase 1/2 results were published July 2025 for its use in patients with ER+/HER2− advanced or metastatic breast cancer (Hamilton et al., 2025).
References
Békés et al., PROTAC targeted protein degraders: the past is prologue. (2022) Nat Rev Drug Discov, Mar;21(3):181-200.
Chirnomas et al., Protein degraders enter the clinic – a new approach to cancer therapy. (2023) Nat Rev Clin Oncol, Mar;21(3):181-200.
Gregory et al., New therapies on the horizon: Targeted protein degradation in neuroscience. (2024) Cell Chem Biol, Sep 19;31(9):1688-1698.
Hamilton et al., Palazestrant, a novel oral Complete Estrogen Receptor Antagonist (CERAN) and Selective Estrogen Receptor Degrader (SERD), in patients with ER+/HER2- advanced or metastatic breast cancer: phase 1/2 study results. (2025) Breast Cancer Res, 2025 Jul 1;27(1):119.
Jochem et al., Degradome analysis to identify direct protein substrates of small-molecule degraders. (2025) Cell Chem Biol, Jan 16;32(1):192-200.
Liu et al., Expanding PROTACtable genome universe of E3 ligases. (2023) Nat Comun, Oct 16;14(1):6509.
Tsai et al., Targeted protein degradation: from mechanisms to clinic. (2024) Nat Rev Mol Cell Biol, Sep;25(9):740-757.
Zhao et al., Targeted protein degradation: mechanisms, strategies and application. (2022) Signal Transduct Target Ther, Apr 4;7(1):113.
