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HKeyBio Industry Commentary
PROTACs and Molecular Glues in Autoimmune Disease
Modality Series 03 | How to Select Preclinical Models
Originally published in Chinese on July 23, 2026.
HKeyBio’s take. Over the past few years, targeted protein degradation (TPD) has been expanding from oncology into immune-mediated inflammatory and autoimmune diseases.
Unlike conventional small-molecule inhibitors, proteolysis-targeting chimeras (PROTACs) and molecular glue degraders use the cell’s own protein degradation machinery to remove a target protein, rather than relying solely on sustained occupancy of its active pocket. A typical PROTAC comprises a target-binding ligand, a linker, and an E3 ubiquitin ligase ligand. Formation of a target–degrader–E3 ligase ternary complex promotes ubiquitination and proteasomal degradation of the target. Molecular glue degraders are generally smaller, monovalent compounds that induce or stabilize a new interaction between a target protein and an E3 ligase.
Why is this attracting interest in autoimmune drug development? Many key autoimmune targets have roles in scaffolding, transcriptional regulation, or the assembly of immune signaling complexes in addition to enzymatic activity. Conventional inhibitors may block only some of these functions, whereas degraders can remove the entire protein, potentially producing deeper and more sustained pathway modulation.
Summary. Reading guide
01 Autoimmune degraders require a connected chain of evidence
02 Why autoimmune drug development needs degradation technologies
03 Align the target, cells, tissues, and endpoints before choosing a model
04 In vivo degrader validation must go beyond efficacy scores
Figure 1. Mechanism of PROTAC-mediated targeted protein degradation. Reproduced from Cardno, Kennedy and Lindon [11], Figure 1, under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). © The Author(s) 2025. Created in BioRender. Cardno, A. (2025), https://BioRender.com/7ggcsvs. POI, protein of interest; Ub, ubiquitin.
This is precisely why model selection for autoimmune degradation programs must go beyond asking, “Which model shows the largest reduction in disease score?” More fundamental questions come first: Is the target protein actually present in the model? Is the E3 ligase expressed at sufficient levels in the target cells? Does the drug actually degrade the protein in disease-relevant tissues? Does degradation translate into beneficial changes in immune mechanisms and disease endpoints? [1,3,10,11]
Without clear answers, even efficacy observed in a disease model may be difficult to attribute to the intended targeted degradation mechanism.
Table 1. Model-selection framework for PROTACs and molecular glues in autoimmune disease.
Development question | What needs preclinical verification? | Model-selection priorities | Key readouts |
Is the target suitable for degradation? | Does the target protein have nonenzymatic, scaffolding, or transcriptional regulatory functions? | Select disease models that reflect the target mechanism. | Target protein expression, cellular localization, pathway activation |
Does degradation actually occur? | Does the drug lower target protein levels in the intended cells and tissues? | First verify cross-species activity and degradation at the cellular level. | Western blot, mass-spectrometry proteomics, flow cytometry, IHC |
Does degradation suppress function? | Does loss of the protein translate into downstream pathway inhibition? | Select models with defined stimulation pathways or immune drivers. | Cytokines, signaling pathways, immune-cell subsets |
Does efficacy match disease endpoints? | Does degradation improve inflammation, tissue injury, or autoantibody-related endpoints? | Choose skin, joint, gut, or other models according to the target mechanism. | Clinical scores, histopathology, inflammatory mediators |
Is safety manageable? | Is there unintended protein degradation, excessive immune suppression, or organ toxicity? | Include observations in non-target tissues, hematology, and immune safety. | Global proteomics, blood counts, immunoglobulins |
IHC, immunohistochemistry.
Figure 2. Comparison of molecular glue degraders and PROTACs and their degradation mechanisms. Supplied composite based on Sasso et al. [12]; mechanism panels reproduce Figure 2 of that article, © 2022 The Authors, under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). The comparison summarizes typical characteristics rather than universal design requirements. Molecular-weight ranges, rule-of-five compliance, target predictability, and binding-affinity requirements vary by compound. PROTACs require suitable binding ligands, but not necessarily catalytic-site ligands; productive ternary-complex formation is also important.
Autoimmune drug development has long faced a challenge: a target may be biologically important, yet conventional inhibition may not adequately control its disease-related functions.
For example, interleukin-1 receptor–associated kinase 4 (IRAK4) has kinase activity and also participates in Myddosome assembly and Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) signaling. Inhibiting its kinase activity alone may not fully address its scaffolding function. In a published Phase 1 study, the IRAK4 degrader KT-474 (SAR444656) demonstrated IRAK4 depletion in blood and skin, functional suppression of TLR/IL-1R signaling, and early clinical activity signals in hidradenitis suppurativa (HS) and atopic dermatitis (AD). The patient cohort was open-label, so these early clinical signals require confirmation. [4]
Figure 3. IRAK4 functions in TLR/IL-1R signaling and the contrasting actions of KT-474 and IRAK4 kinase inhibitors. Supplied excerpt from Ackerman et al. [4], Extended Data Figure 1a. © 2023 Kymera Therapeutics, Inc.
The significance of this example is the need to connect protein depletion, pathway inhibition, and improvement in tissue inflammation, rather than relying solely on in vitro enzyme inhibition assays. [4,13]
Bruton’s tyrosine kinase (BTK) illustrates a similar rationale. BTK participates in B-cell receptor, Fc receptor (FcR), and some innate immune signaling pathways, making it relevant to systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and antibody-mediated inflammation. Conventional BTK inhibitors primarily block kinase activity, whereas BTK degraders may remove both catalytic and noncatalytic functions. Published preclinical work has reported reduced inflammation in collagen-induced arthritis (CIA) and reductions in autoantibody-related measures in lupus-like disease models. The CIA evidence cited here includes a conference abstract, while the lupus-like model findings were reported in a peer-reviewed study. [5–7]
Representative molecular-glue approaches in autoimmunity include cereblon E3 ligase modulators. Iberdomide promotes degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are linked to immune-cell development, autoantibody production, and genetic susceptibility to SLE. A Phase 2 SLE trial published in the New England Journal of Medicine reported a higher SLE Responder Index 4 (SRI-4) response rate in a specified dose group than with placebo. [8,9]
These clinical findings support transcription-factor degradation as a potential therapeutic approach for SLE and related diseases. They do not mean that all molecular glues are suitable for autoimmune indications, or that more extensive degradation is necessarily safer.
The value of PROTACs and molecular glues in autoimmunity therefore goes beyond novelty. They may address three problems that are difficult for conventional inhibitors: the lack of an ideal catalytic pocket for inhibition, the presence of nonenzymatic target functions, and disease mechanisms that require deeper or more sustained control at the protein level. [1,2,10,12]
They also introduce development challenges: difficult tissue distribution, limited cell permeability, differences in E3 ligase expression, unintended substrate degradation, uncertain protein-recovery kinetics, and an incompletely defined margin for prolonged immune suppression. Appropriate preclinical models are needed to investigate these issues early. [10,11]
For a PROTAC or molecular glue program, the first question is not, “Should we use CIA, dextran sulfate sodium (DSS), or imiquimod (IMQ)?” It is, “In which immune cells does this target drive disease? In which diseased tissues are those cells located? Can the candidate degrader reach these cells and tissues? Which functional endpoints should change after target protein degradation?”
Focus on inflammatory settings driven by TLR/IL-1R signaling. Skin inflammation, HS-related inflammation, AD-like inflammation, and inflammatory bowel disease (IBD)-associated mucosal inflammation may be informative, provided that the model has demonstrable TLR/IL-1R pathway activation and allows measurement of IRAK4 protein degradation and downstream inflammatory mediators such as IL-6, IL-8, and tumor necrosis factor (TNF). Readouts must be appropriate to the species; for example, mice do not have a direct IL-8/CXCL8 ortholog, so relevant chemokine readouts must be selected instead. [14]
Select models aligned with B-cell, FcR, and autoantibody-driven disease biology. CIA, collagen antibody-induced arthritis (CAIA), and SLE or lupus-nephritis models may be more informative than a generic acute inflammation model, when their mechanisms match the program. Endpoints should extend beyond joint scores to B-cell subsets, plasma cells, autoantibodies, immune complexes, and FcR-associated myeloid-cell activation.
Focus on B cells, plasma cells, plasmacytoid dendritic cells (pDCs), T cells, and type I interferon signaling. SLE, cutaneous lupus, and models of aberrant B-cell activation offer greater translational relevance for these mechanisms. Because these targets influence immune-cell development and transcriptional regulation, preclinical evaluation should examine immune-cell composition, interferon gene signatures, autoantibodies, and hematological safety alongside disease scores.
For conventional small-molecule inhibitors, development teams typically examine plasma drug concentrations, target inhibition, downstream signaling, and disease scores. PROTACs and molecular glues require an additional core measurement: whether the target protein has actually been degraded, and how long that degradation persists.
This calls for more detailed pharmacokinetic/pharmacodynamic (PK/PD) design. Plasma exposure does not establish degradation in tissue. Target mRNA levels need not fall in parallel with the protein, so transcript measurements alone generally cannot demonstrate degradation. Ideally, target protein levels should be measured directly in relevant compartments, such as blood, spleen, lymph nodes, skin, gut, and joint synovium. [1,10,11]
The exposure–response relationship may also differ from that of conventional inhibitors. PROTACs and molecular glue degraders have event-driven pharmacology: once the target is depleted, functional recovery depends on the rate of protein resynthesis. Biological effects can therefore persist after drug concentrations decline. In an in vivo proof-of-concept (PoC) study, achieving maximum target degradation (Dmax) in diseased tissue and maintaining that effect is often more important than pursuing high plasma exposure alone. [1,10]
Species differences are another consideration. Strong degradation in human-derived cells does not guarantee activity in a mouse model. Before an animal efficacy study, target protein degradation should first be confirmed in cells from the intended test species. [10,11]
Safety is equally central. Degraders remove the protein rather than simply inhibiting one function, and molecular glues may induce degradation of unintended neosubstrates. In vivo validation should therefore evaluate hematology, longitudinal immune-cell changes, immunoglobulins, infection-risk-related indicators, and histopathology alongside efficacy.
When degradation technologies enter autoimmune drug development, model selection needs to move beyond demonstrating efficacy toward linking degradation, mechanism, and disease. We see a central change in the purpose of preclinical validation: models must help explain whether degradation produces a mechanistic benefit as well as showing a therapeutic effect.
A more informative validation path begins by confirming degradation and functional suppression in the intended human immune cells, followed by verification that the target protein and E3 ligase are suitable in the animal species. Disease models should then be selected according to the target mechanism. During in vivo PoC, measure exposure, target protein degradation, downstream pathway inhibition, histopathology, and disease endpoints together. Finally, add long-term dosing, relapse models, and safety observations according to the intended clinical use.
For an IRAK4 degrader, connect the evidence around TLR/IL-1R-driven inflammation. For a BTK degrader, connect B-cell biology, autoantibodies, FcR signaling, and inflammatory tissue injury. For an IKZF1/IKZF3 molecular glue, connect SLE-relevant immune cells, interferon signaling, and hematological safety. Different targets require different models; there is no universal autoimmune degrader model.
The long-term contribution of degradation technologies to autoimmune treatment depends on demonstrating more precise protein-level control in the appropriate cells, tissues, and disease stage, beyond stronger inhibition alone.
PROTACs and molecular glues open new possibilities for autoimmune drug development, and those possibilities require rigorous validation. New modalities call for more complete in vivo evidence. Selecting a model for an autoimmune degrader means choosing one that can explain why degradation is effective, where it works, for whom it works, and whether it is safe.
[1] Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022;21:181–200. doi:10.1038/s41573-021-00371-6. Source
[2] Zhao L, et al. Targeted protein degradation: mechanisms, strategies and application. Signal Transduct Target Ther. 2022;7:113. doi:10.1038/s41392-022-00966-4. Source
[3] Tan X, et al. Molecular glue-mediated targeted protein degradation: A novel strategy in small-molecule drug development. iScience. 2024;27(9):110712. doi:10.1016/j.isci.2024.110712. Source
[4] Ackerman L, et al. IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial. Nat Med. 2023;29:3127–3136. doi:10.1038/s41591-023-02635-7. Source
[5] Song Y, et al. Targeted protein degradation in autoimmune diseases: from mechanisms to therapeutic breakthroughs. J Autoimmun. 2025;156:103475. doi:10.1016/j.jaut.2025.103475. Source
[6] Zhu C, et al. PROTAC for Bruton’s tyrosine kinase degradation alleviates inflammation in autoimmune diseases. Cell Discov. 2024;10:82. doi:10.1038/s41421-024-00711-x. Source
[7] Robbins D, et al. POS0006 NX-5948, a selective degrader of BTK, significantly reduces inflammation in a model of autoimmune disease. Ann Rheum Dis. 2021;80(Suppl 1):204–205. Conference abstract. doi:10.1136/annrheumdis-2021-eular.1675. Source
[8] Merrill JT, et al. Phase 2 trial of iberdomide in systemic lupus erythematosus. N Engl J Med. 2022;386:1034–1045. doi:10.1056/NEJMoa2106535. Source
[9] Schafer PH, et al. Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus. Ann Rheum Dis. 2018;77:1516–1523. doi:10.1136/annrheumdis-2017-212916. Source
[10] Tsai JM, et al. Targeted protein degradation: from mechanisms to clinic. Nat Rev Mol Cell Biol. 2024;25:740–757. doi:10.1038/s41580-024-00729-9. Source
[11] Cardno A, Kennedy B, Lindon C. Cellular parameters shaping pathways of targeted protein degradation. Commun Biol. 2025;8:691. doi:10.1038/s42003-025-08104-w. Source
[12] Sasso JM, Tenchov R, Wang DS, et al. Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic. Biochemistry. 2023;62(3):601–623. doi:10.1021/acs.biochem.2c00245. Source
[13] Ferguson FM. PROTACs reach clinical development in inflammatory skin disease. Nat Med. 2023;29:3006–3007. doi:10.1038/s41591-023-02622-y. Source
[14] Shibata K, Nomiyama H, Yoshie O, Tanase S. Genome diversification mechanism of rodent and Lagomorpha chemokine genes. Biomed Res Int. 2013;2013:856265. doi:10.1155/2013/856265. Source
Author: HKeyBio Marketing Department | Scientific review: Jing Yan | Editor: Wang Shuyan
HKeyBio, the autoimmune disease model specialist, is a preclinical contract research organization (CRO) focused on autoimmune and allergic diseases, providing end-to-end in vivo efficacy evaluation services. Its core technical team has more than 20 years of experience across the autoimmune drug development process. The company is ISO 9001 certified and operates an integrated research facility in Suzhou Industrial Park covering molecular and cellular research, pathology, small-animal studies, and analytical testing, alongside two nonhuman primate research sites in Suzhou and Guangxi. HKeyBio has nearly 80 employees, and all project leaders hold master’s or doctoral degrees. The team has accumulated experience supporting more than 500 investigational new drug (IND) applications in autoimmune diseases, enabling it to efficiently address complex challenges throughout autoimmune drug development and regulatory submission.
· 50+ nonhuman primate models of autoimmune and allergic diseases
· 500+ animal models of autoimmune and allergic diseases
· Experience supporting 500+ IND applications in autoimmune diseases
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