Future Trends in Protein Degrader Research

Targeted protein degradation (TPD) uses small molecules to induce the selective degradation of proteins by recruiting ubiquitin E3 ligases to target proteins of interest, resulting in their ubiquitylation and proteasomal degradation. There are two main classes of TPD therapeutics: bifunctional PROTACs and molecular glue degraders, each with their own advantages and challenges. A new review written by Jonathan Tsai and larger team at the Brigham and Women's Hospital covers the current landscape of TPD approaches, their parallels in biological processes, the ongoing clinical exploration of novel degraders, and future directions of the field. Checkout the link to the full paper and a brief summary below: Targeted protein degradation from mechanisms to clinic. https://lnkd.in/dYZufUHt Serendipitous discovery of new protein degraders: A key catalyzing event for the TPD field was the clinical proof of concept provided by the unexpected discovery that thalidomide derivatives like lenalidomide induce degradation of the transcription factors IKZF1 and IKZF3, which underlies their efficacy in multiple myeloma. Structural studies revealed thalidomide derivatives bind to cereblon and reshape its surface to enable recruitment of neo-substrates containing a glycine degron. This led to the development of many new cereblon-based molecular glues and PROTACs. Discovery of novel molecular glues: Given the clinical success of molecular glue degraders, there is high interest in discovering new molecular glues beyond thalidomide derivatives. One rational approach identified small molecules that enhance the interaction between beta-catenin and its natural E3 ligase SCF-beta-TrCP. Another approach is diversifying known molecular glue scaffolds like thalidomide to identify new neo-substrates, which has led to selective degraders of the transcription factor IKZF2. Clinical perspectives: Despite the mechanistic diversity of TPD, relatively few degrader drugs are currently FDA-approved. However, many molecular glues and PROTACs are now in clinical development for indications like cancer and autoimmune disorders. Molecular glues are being tested in hematologic and solid tumors, while PROTACs are being developed for a wider range of targets like kinases, nuclear receptors, and apoptotic proteins. The clinical success of thalidomide derivatives has established TPD as a viable therapeutic modality, but also revealed some potential safety concerns like embryotoxicity that must be monitored. Resistance mechanisms to degraders are starting to be uncovered, including mutations in E3 ligases or upregulation of efflux pumps. TPD is also being explored in other diseases beyond cancer, such as neurodegenerative and infectious diseases. Ultimately, the versatility of TPD approaches has greatly expanded the druggable proteome and is poised to deliver many novel therapeutics in the years ahead.

Very bullish on the rational functionalization of protein surfaces w/ small molecules. Looking at monte rosa’ s vav1 degrader and revmed's cyclophilin-based molecular glue work, we’re getting a glimpse a world where any intracellular protein surface can be drugged, and where sm drug discovery starts to conceptually resemble antibody discovery. Antibodies are essentially rigid scaffolds used to present a diverse set of small loops; this system allows a single structural format to bind with high-affinity to ~ the entire proteome; scientists have developed rational screening systems (immunization, surface display etc…) to quickly find binders of interest.   There’s a growing appreciation that certain intracellular proteins can act as useful scaffolds for small molecule drugs. Monte rosa has realized that the degradative activity of cereblon can be redirected to a huge variety of targets, so long as they contain  a simple G-loop motif; revmed has seen how the cyclophilin protein surface can be co-opted to help a small molecule inhibit ras. In both cases: - binding specificity is driven by the sm but critically supported by interactions between POI and the ‘sm protein scaffold.’ - intracellular sm accumulation can be promoted by interaction with a high-abundance protein scaffold. - real POC is accumulating on the generalizability of this approach across targets—not quite as straightforward as antibody discovery, but still generalizable. It should be possible to DEL-ify custom-made sm libraries and screen for binders in the presence of cereblon/cyclophin and target of interest.  

🌟 𝗘𝘅𝗽𝗮𝗻𝗱𝗶𝗻𝗴 𝘁𝗵𝗲 𝗣𝗥𝗢𝗧𝗔𝗖 𝗧𝗼𝗼𝗹𝗯𝗼𝘅: 𝗔 𝗡𝗲𝘄 𝗘𝟯 𝗟𝗶𝗴𝗮𝘀𝗲 𝗳𝗼𝗿 𝗧𝗮𝗿𝗴𝗲𝘁𝗲𝗱 𝗣𝗿𝗼𝘁𝗲𝗶𝗻 𝗗𝗲𝗴𝗿𝗮𝗱𝗮𝘁𝗶𝗼𝗻 🌟 Proteolysis-targeting chimeras (PROTACs) have revolutionized drug discovery by degrading disease-driving proteins rather than inhibiting them. However, as discussed in one of last weeks posts, the overreliance on just two E3 ligases—Cereblon (CRBN) and Von Hippel-Lindau (VHL)—limits therapeutic potential. A new study by Yang et al. (2025) presents ZYG11B, a substrate receptor of the CRL2 complex, as a novel E3 ligase for PROTAC applications. This finding opens the door for aptamer-based PROTACs (ZATACs), a novel degrader class that offers improved precision and efficacy. 🔑 𝗞𝗲𝘆 𝗛𝗶𝗴𝗵𝗹𝗶𝗴𝗵𝘁𝘀 𝗔𝗽𝘁𝗮𝗺𝗲𝗿-𝗕𝗮𝘀𝗲𝗱 𝗗𝗲𝗴𝗿𝗮𝗱𝗲𝗿𝘀 𝗨𝗻𝗹𝗼𝗰𝗸 𝗮 𝗡𝗲𝘄 𝗠𝗲𝗰𝗵𝗮𝗻𝗶𝘀𝗺: Unlike traditional PROTACs, which use small-molecule ligands, this study identifies Apt#Z6, a DNA aptamer that binds ZYG11B without inhibiting its function—enabling targeted degradation without interfering with natural E3 activity. 𝗧𝘂𝗺𝗼𝗿-𝗦𝗽𝗲𝗰𝗶𝗳𝗶𝗰 𝗗𝗲𝗹𝗶𝘃𝗲𝗿𝘆 𝗘𝗻𝗵𝗮𝗻𝗰𝗲𝘀 𝗦𝗲𝗹𝗲𝗰𝘁𝗶𝘃𝗶𝘁𝘆: Three-way junction-based ZATACs (3WJ-ZATACs) incorporate tumor-targeting aptamers to accumulate in cancer cells, minimizing off-target toxicity selectively. 𝗘𝘅𝗽𝗮𝗻𝗱𝗶𝗻𝗴 𝘁𝗵𝗲 𝗣𝗥𝗢𝗧𝗔𝗖 𝗧𝗮𝗿𝗴𝗲𝘁 𝗦𝗽𝗮𝗰𝗲: 3WJ-ZATACs successfully degrade oncogenic proteins previously deemed undruggable, including: ✔ SOX2, a key regulator in lung cancer. ✔ Mutant p53-R175H, a driver of aggressive tumors. ✔ Nucleolin (NCL), implicated in multiple malignancies. 𝗣𝗿𝗲𝗰𝗹𝗶𝗻𝗶𝗰𝗮𝗹 𝗩𝗮𝗹𝗶𝗱𝗮𝘁𝗶𝗼𝗻: ZATACs exhibited potent anti-tumor activity, reducing cancer cell proliferation and significantly inhibiting tumor growth in xenograft models. Selective in vivo accumulation further confirmed their tumor-targeting capability. 💡 𝗪𝗵𝘆 𝗧𝗵𝗶𝘀 𝗠𝗮𝘁𝘁𝗲𝗿𝘀 This study reinforces the need to systematically expand the E3 ligase landscape for targeted degradation. Building on the PROTACtable genome this raises critical next steps: 𝗪𝗵𝗶𝗰𝗵 𝗘𝟯 𝗹𝗶𝗴𝗮𝘀𝗲𝘀 𝗼𝗳𝗳𝗲𝗿 𝘁𝗶𝘀𝘀𝘂𝗲-𝗿𝗲𝘀𝘁𝗿𝗶𝗰𝘁𝗲𝗱 𝗲𝘅𝗽𝗿𝗲𝘀𝘀𝗶𝗼𝗻 𝘁𝗼 𝗺𝗶𝗻𝗶𝗺𝗶𝘇𝗲 𝘁𝗼𝘅𝗶𝗰𝗶𝘁𝘆? 𝗛𝗼𝘄 𝗱𝗼 𝗺𝘂𝗹𝘁𝗶-𝗹𝗶𝗴𝗮𝘀𝗲 𝘀𝘁𝗿𝗮𝘁𝗲𝗴𝗶𝗲𝘀 𝗶𝗺𝗽𝗿𝗼𝘃𝗲 𝗣𝗥𝗢𝗧𝗔𝗖 𝗿𝗲𝘀𝗶𝘀𝘁𝗮𝗻𝗰𝗲 𝗽𝗿𝗼𝗳𝗶𝗹𝗲𝘀? 𝗛𝗼𝘄 𝗱𝗼 𝘄𝗲 𝗮𝗹𝗶𝗴𝗻 𝘁𝗵𝗲 𝗘𝟯 𝗹𝗶𝗴𝗮𝘀𝗲 𝗹𝗮𝗻𝗱𝘀𝗰𝗮𝗽𝗲 𝘄𝗶𝘁𝗵 𝗣𝗥𝗢𝗧𝗔𝗖 𝗱𝗲𝘀𝗶𝗴𝗻 𝘀𝘁𝗿𝗮𝘁𝗲𝗴𝗶𝗲𝘀? ZATACs represent a significant advancement in PROTAC design, but they are just the beginning. The real question isn’t, “Which ligases could we use?”—it’s, “Which ligases should we use to maximize therapeutic impact?” Is this the future of precision protein degradation? Let’s discuss. 👇 📄 𝗥𝗲𝗮𝗱 𝘁𝗵𝗲 𝘀𝘁𝘂𝗱𝘆: https://lnkd.in/e6PX8XE7 #PROTACs #TargetedDegradation #E3Ligases #DrugDiscovery #CancerTherapeutics #PrecisionMedicine #ProteinDegradation

Induced Proximity is a captivating concept that has revolutionized drug discovery by enabling researchers to target proteins previously considered undruggable. Emerging technologies like RNA-degraders are particularly intriguing because of their novelty. A patent application by Arrakis Therapeutics, a frontrunner in this field, for CCR4-NOT binding RNA degraders published yesterday caught my attention. Here is the link to the document: https://lnkd.in/gFHpyGNK The CCR4-NOT complex is an essential, multifunctional protein complex that regulates various cellular processes. As a pivotal element in mRNA metabolism, it controls gene expression at multiple stages—from transcription in the nucleus to mRNA degradation in the cytosol. In mammals, it primarily functions as a deadenylase, shortening the poly(A) tails of mRNA, which leads to their degradation. Arrakis Therapeutics has described bifunctional molecules in their patent application that bind to specific RNA transcripts and recruit RNA-binding proteins to initiate RNA degradation. Their most potent compound demonstrated a 7.3-fold increase in activity over DMSO in a biochemical AMP-glo assay. This field holds great promise for future drug development. To keep abreast of the latest patent literature and learn about currently trending targets, visit our Patent Highlights at Drug Hunter https://lnkd.in/gubY9UV2

Rational Chemical Design of Molecular Glue Degraders Targeted protein degradation with molecular glue degraders has arisen as a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. However, we currently lack rational chemical design principles for converting protein-targeting ligands into molecular glue degraders. To overcome this challenge, we sought to identify a transposable chemical handle that would convert protein-targeting ligands into molecular degraders of their corresponding targets. Using the CDK4/6 inhibitor ribociclib as a prototype, we identified a covalent handle that, when appended to the exit vector of ribociclib, induced the proteasome-mediated degradation of CDK4 in cancer cells. Further modification of our initial covalent scaffold led to an improved CDK4 degrader with the development of a but-2-ene-1,4-dione (“fumarate”) handle that showed improved interactions with RNF126. Subsequent chemoproteomic profiling revealed interactions of the CDK4 degrader and the optimized fumarate handle with RNF126 as well as additional RING-family E3 ligases. We then transplanted this covalent handle onto a diverse set of protein-targeting ligands to induce the degradation of BRD4, BCR-ABL and c-ABL, PDE5, AR and AR-V7, BTK, LRRK2, HDAC1/3, and SMARCA2/4. Our study undercovers a design strategy for converting protein-targeting ligands into covalent molecular glue degraders. https://lnkd.in/ecbvqqv6

#drugdesign #drugdiscovery #compchem #computationalchemistry #drugdevelopment #protacs Structure-Based Design of CBP/EP300 Degraders: When Cooperativity Overcomes Affinity An open access article by Cheng-Sanchez et al. (Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland). "In this work, the authors report the discovery and characterization of a novel CBP/EP300 degrader dCE-2. This PROTAC is based on an in-house-developed CBP/EP300 ligand, 3 (KD CBP/EP300 = 29/25 nM). The development of the small-molecule ligand 3 was based on an unprecedented 3-methylcinnoline acetyl-lysine mimic identified by high-throughput docking, followed by fragment growing and subsequent optimization based on the crystal structure of a closely related analogue. The protein structure-based analysis enabled the identification of a suitable attachment point within this ligand, which upon connection to a 10-atom aliphatic linker and a thalidomide CRBN E3 ligand resulted in dCE-2. Interestingly, this PROTAC is active across multiple cell lines (LP1, MM1S, LNCaP, and SH-SY5Y) reaching its peak performance after 16 h (DC50 = 40 nM in LP1 cells). Furthermore, we show that dCE-2 can form a ternary complex with CBP and CRBN both in cellulo (FluoPPI) and in vitro (TR-FRET) with high cooperativity (α = 3.4). Notably, MD simulations helped rationalize why despite the modest KD values of dCE-2 toward CBP/EP300 bromodomains, this PROTAC could degrade both proteins in a highly efficient manner: its ability to switch between a compact and an extended conformation might impair binding in biochemical assays but guarantee improved cell permeability. Thus, in contrast to small-molecule inhibitor development, binary affinity should not be the only parameter in early PROTAC screening. Collectively, these results led to the development of a novel CBP/EP300 PROTAC that further expands the toolbox of chemical probes to deconvolute the role of such proteins in disease development." JACS Au Open Access https://lnkd.in/eZKh42uh

Amphista Therapeutics' technology originates from the TPD expertise of Alessio Ciulli's lab at the University of Dundee. Unlike the first-generation degraders (PROTACs), which have limitations like challenges in optimizing oral bioavailability, limited to CRBN, poor CNS penetration, and overall poor drug-like properties, Amphista's unique molecular glues offer broad advantages. Amphista's innovative mechanistic approach and chemistry-driven strategy enable the development of TPD drugs with improved drug-like properties, providing oral bioavailability, effective tissue penetration, and expanding the development scope of first-in-class drugs targeting a wide range of challenging diseases (including oncology, immunology, CNS disorders, and other areas involving diseases that are difficult to tackle with initial TPD methods). Consequently, the company positions itself as a leader in next-generation TPD methods. On January 24, 2024, Amphista announced successful delivery of multiple degraders to the CNS, demonstrating significant target protein degradation in the brain. Apart from showing significant activity in tumor models, Amphista has also made substantial progress in neurodegenerative disease technology. On May 23, 2024, at the Protein Degradation Focus Symposium, Amphista revealed a new differentiated mechanism of action for BRD9 degradation: a bifunctional BRD9 degrader selectively induces proximity between BRD9 and DCAF16, acting as a molecular glue, leading to rapid and robust degradation of BRD9. Given Amphista’s limited public disclosures, delving into its technology platform necessitates examining its patents. Initially, it was believed that Amphista's technology involved discovering new E3 ligases, but a review of its patent list suggests otherwise. UCHL5, USP14, RPN11—three deubiquitinating enzymes (DUBs). How do these induce degradation? Those familiar with the TPD field might recognize the recently emerging opposing mechanism: Targeted Protein Stabilization (TPS), with Deubiquitinase Targeting Chimeras (DUBTACs) as a notable example. DUBTACs consist of a target protein ligand, a DUB ligand, and a linker, which together bind the target protein and DUB, removing ubiquitin chains from the target protein to stabilize its level against ubiquitin-dependent degradation. The mechanism of DUBTACs is clearly at odds with protein degradation, so how does Amphista achieve protein degradation through DUBs? Investigating the commonality among UCHL5, USP14, and RPN11 reveals that they are key DUBs in the 19S subunit of the 26S proteasome. Following this lead, one can find an article that might explain the mechanism: Genentech's 2022 publication in Nature Chemical Biology on a new TPD mechanism involving direct recruitment of the 26S proteasome for targeted degradation [Nat Chem Biol 19, 55–63 (2023)]. （Please check the comments for the rest.）

Characterization of PROTAC specificity and endogenous protein #interactomes using ProtacID Researchers from the Princess Margaret Cancer Centre and University of Toronto have developed a proximity-dependent biotinylation based approach to identify PROTAC-proximal proteins in living cells (ProtacID) This approach enabled the team to: - Validate genuine degradation targets (like SMARCA4 in BAF complexes) across multiple PROTACs and cell lines - Identify non-productive interactions (e.g., KIF20B binding without degradation) - Characterize endogenous protein complexes (including PRC2 and BET complexes) without antibody reliance or protein tagging. The ProtacID approach addresses critical challenges in #PROTAC development by revealing both productive degradation pathways and off-target interactions - crucial insights for designing safer, more effective protein degraders. Global proteome analysis was conducted on an Evosep One (Evosep Biosystems) coupled to a Bruker timsTOF HT mass spectrometer. The full manuscript can be read here: https://lnkd.in/eAvM5QXG Suman Shrestha, Matthew Maitland, Ph.D., Echo J., Shili Duan, David Y. Nie, Jonathan St-Germain, PhD, Dalia Barsyte-Lovejoy, Cheryl Arrowsmith, Brian Raught #PROTACs, #DrugDiscovery, #Proteomics, #TargetedProteinDegradation #TPD #Evosep #ubiquitin #BioID

Exciting Advances in Targeted Protein Degradation! Recent work highlights the design, synthesis, and validation of NU-PRO-1—a first-in-class PROTAC engineered to degrade telomerase reverse transcriptase (TERT), a central player in cancer cell immortality and therapy resistance. Utilizing structure-based design and the covalent chrolactomycin analog NU-1, researchers developed a bifunctional molecule that recruits the VHL E3 ligase to TERT, resulting in its targeted ubiquitin-proteasome-mediated degradation. Unlike traditional inhibitors, NU-PRO-1 eliminates both the catalytic and non-catalytic functions of TERT, demonstrating superior radiosensitization in cancer cell models. 🔑 Key Highlights: - Structure-guided covalent PROTAC design leveraging high-resolution cryo-EM hTERT models - Potent, selective, and transient TERT degradation in cancer cells - Enhanced DNA damage response and radiosensitization compared to TERT inhibition alone This approach opens new possibilities for overcoming cancer therapy resistance and provides valuable insights into TERT’s diverse roles in cancer biology. #DrugDiscovery #PROTAC #CancerResearch #TargetedTherapies #ProteinDegradation #Telomerase #Radiosensitization #MedicinalChemistry https://lnkd.in/gK_CekYs

Christopher Parker and AbbVie published a preprint on target-agnostic PROTACs or "AgnoTACs" comprising diverse target-binding moieties, various linkers, and a CRBN ligand to explore the CRBN-degradable proteome in a target-unbiased fashion. Proteomic profiling of this library identified >50 proteins that were degraded by these bifunctional molecules, revealing potential starting points for PROTAC degrader development. https://lnkd.in/gjk_DA5g