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Open research questions in Protein Degradation and Inhibitors

31 unresolved questions extracted from the limitations and future-work sections of 155 Protein Degradation and Inhibitors papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Performance comparisons show that different systems prioritize varying factors, such as targeting precision, response rates, or drug-loading ratios, necessitating tailored designs based on specific clinical indications. Importantly, future development of nano-TPD systems should move beyond conceptual optimization toward clinically translatable design principles. Based on the performance analysis and key challenges discussed above, translation success will likely depend on three coordinated dimensions: patient stratification and biomarker-guided activation, predictable in vivo fate and safety profiling, and manufacturability under defined regulatory frameworks. Future research should emphasize personalized treatment strategies and technological optimization to advance nano-TPD applications in precision medicine. Individualized design strategies will become critical, especially through integrating actual microenvironment parameters from patient lesions, enabling customized nano-TPD systems. Accurately understanding patient-specific tumor or lesion characteristics will support developing personalized nanosystems that match biomarkers and therapeutic needs, significantly enhancing targeting accuracy and treatment efficacy[175,176]. Building on this foundation, to further boost translational feasibility, a more clinically actionable strategy can prioritize biomarker-defined patient subgroups and establish PK/PD-linked activation windows - ensuring that the responsiveness of nano-TPD systems aligns with quantifiable clinical parameters. This approach is expected to mitigate heterogeneity-induced variability and improve the reproducibility of therapeutic outcomes across diverse patient populations. Additionally, increasing complexity in disease diagnosis and treatment emphasizes the need to optimize intelligent response mechanisms. Future studies should focus on advanced logic-gate response systems (e.g., “AND/OR/NOT” composite logic) that intelligently trigger responses based on multiple lesion features, substantially enhancing lesion identification and therapeutic responsiveness. These intelligent systems can rapidly respond to dynamic lesion changes, achieving efficient protein degradation and disease control[177-179]. Of course,system complexity must be balanced with manufacturability and regulatory feasibility. Page 26 of 34 Liu et al. Microstructures 2026, 6, 2026084 Overengineered logic-gate systems may face significant scale-up, quality control, and comparability challenges under current regulatory frameworks for nanomaterials and combination products. Thus, future intelligent designs should integrate QbD principles from early-stage development to ensure defined CQAs and scalable production pathways. In technological advancements, innovations in multimodal characterization techniques will become essential.

    Nano-TPD for precision protein degradation via endogenous or exogenous triggered release · 2026 · DOI

  • less-studied diseases Looking forward, three priorities follow from the work assembled in this Research Topic. First, generalizable, multi- cohort datasets—particularly and in underrepresented populations—are essential to test whether AI- derived biomarkers are robust beyond their training environments. Second, mechanistic interpretability must continue to be a first-class objective alongside predictive performance; biomarkers that cannot be linked back to plausible biology will struggle to attract clinical and the field must move past regulatory confidence. Third, demonstration projects toward implementation science: cost- effectiveness analyses, health-system integration studies, and pragmatic trials of AI-enabled biomarker-guided care. We are grateful to the authors for their thoughtful contributions, to the reviewers whose careful evaluations have shaped the quality of this Research Topic, and to the editorial staff at Frontiers in Pharmacology for their support throughout the development of this Research Topic. We hope that the studies gathered here will both inform and challenge readers, and that they will help accelerate the integration of traditional pharmacological rigor with the analytical reach of artificial intelligence.

    Editorial: Advances in biomarkers and drug targets: harnessing traditional and AI approaches for novel therapeutic mechanisms · 2026 · DOI

  • Ubiquitination proceeds through the transfer of ubiquitin from UCEs to substrate lysines, but the specificity of lysine ubiquitination has not been widely investigated in cells.

    Site-specific combinatorial ubiquitination drives the targeted degradation of plasma membrane proteins · 2026 · DOI

  • Although there is a growing demand for the treatment of muscle-related diseases, the number of suitable target proteins for TPD is currently limited to a few, such as DUX462, Dysferlin63, and MSI264.

    Discovery of a KLHL41 Ligand for Muscle Specific Protein Degradation · 2026 · DOI

  • The nanoluciferase and HiBiT assays are described for specific cell lines (MM.1S, SK-N-DZ, HSPC), but the generalizability to other cell types and disease models is not addressed.

    A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader · 2026 · DOI

  • While the paper describes assays for multiple targets (IKZF3, SALL4, BRD4, Ikaros), the breadth of additional CRBN substrates that could be evaluated with the dihydrouracil ligand approach remains unexplored.

    A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader · 2026 · DOI

  • The TMT labelling experiments were conducted separately for different G4L-PROTAC compounds (experiments 1 and 2), which may limit cross-experiment comparisons and could introduce batch effects.

    Degradation of G-quadruplex-binding proteins in chromatin using G4-ligand-based proteolysis-targeting chimeras · 2026 · DOI

  • The study used a one-site binding model for Kd value calculations in ELISA experiments, which may not capture more complex binding mechanisms that could occur in chromatin contexts.

    Degradation of G-quadruplex-binding proteins in chromatin using G4-ligand-based proteolysis-targeting chimeras · 2026 · DOI

  • The balance between stability in circulation and rapid intracellular cleavage remains central to successful ADC design, but optimization strategies are not fully elucidated.

    Emerging Drug Modalities Redefining Small-Molecule Therapeutics: Antibody–Drug Conjugates, Protacs, and Molecular Glues · 2026 · DOI

  • There will be a need for worldwide collaboration and innovative study design to validate biomarkers and develop precision epigenetics because of the relative rarity of many epigenetically driven cancers.

    Chromatin Addiction in NUT Carcinoma: Targeted Epigenetic Pharmacology Beyond BET Inhibition · 2026 · DOI

  • Given its relevant role in tumorigenesis and cancer progression, AKT represents an intensely pursued therapeutic target in oncology. [14,48,49] The recent clinical approval of Capivasertib marked a ground-breaking milestone in the field of AKT-targeted therapies, revealing the clinical relevance of this critical protein kinase. Nevertheless, due to the highly complex and dynamic nature of the AKT signalling network, involving multiple key multifunctional downstream nodes and cross-talks with other major cellular signalling pathways, achieving durable cellular responses and significant therapeutic effects through monotherapy has proved to be challenging. [1,14,48,50] Arising as a new modality at the forefront of AKT modulation, PROTAC-mediated AKT-targeted protein degradation has undoubtedly revealed substantial advantages and improved profiles relative to conventional AKT inhibition. Numerous potent orthosteric and allosteric AKT-targeting PROTACs enabling remarkable activities and promising properties both in vitro and in vivo were reported. Harnessing a unique catalytic mechanism of action, AKT degraders had the potential to surpass the major limitations associated with the AKT inhibitors, fostering enhanced efficacy whilst significantly reducing dose-limiting toxic effects. Acting at sub-stoichiometric doses, AKT PROTACs boasted greater potency, by sustaining robust destabilisation and inactivation of AKT proteins at substantially lower doses. [9,13,16,17] Besides, as illustrated by some of the AKT PROTACs described above, intracellular specific degradation of AKT proteins proved to dissociate pharmacodynamics from pharmacokinetics. As a matter of fact, degrading rather than inhibiting allows to transiently erase AKT proteins from the cell, eliminating both the catalytic and kinase-independent functions of the protein and obligating the cell to rely on the re-synthesis rate of the protein itself to restore the protein functionality. [9,15,48] Enabled by the slow turnover of AKT proteins, AKT PROTACs were thus revealed to achieve more robust and durable downstream effects, resulting in enhanced and long-lasting pharmacological effects. [9,12] Amongst the others, this was significantly showcased in the seminal work performed by You et al. where they demonstrated that the effects induced by their pan-AKT degrader were retained for up to 96 hours. An additional potential value of the AKT PROTACs over the inhibitors is the greater selectivity driven by this modality. Indeed, PROTACs demonstrated to substantially exceed the selectivity of their constitutive POI ligands discerning amongst highly homologous isoforms within the same target protein.

    Expanding The Scope of AKT Modulation Through Targeted Protein Degradation · 2026 · DOI

  • However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors.

    Targeting cancer with small-molecule pan-KRAS degraders · 2024 · DOI

  • Although kinase inhibitors targeting upstream oncogenic drivers can produce clinical benefit, responses are often limited by acquired resistance and pathway adaptation.

    Abstract B045: Targeted degradation of cyclin T1 constrains transcription elongation and triggers tumour cell apoptosis · 2026 · DOI

  • The paper references crystal structure data and proteomics results but does not explicitly discuss limitations in structural coverage or the completeness of the proteomics dataset for understanding off-target effects.

    A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader · 2026 · DOI

  • The excerpt provided is primarily methodological detail and data availability statements from the latter portion of the paper, lacking explicit discussion of research gaps, limitations, or future work directions.

    A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader · 2026 · DOI

  • As both native recognition mechanisms and novel molecular glues are characterized, new opportunities will continue to emerge, further extending the design space of drug discovery.

    Molecular Glue Degraders and the Expanding Design Space of Drug Discovery · 2026 · DOI

  • Beyond protein degradation outcomes, the underlying logic of molecular glue-induced recognition rewiring is more general and applicable to other cellular fates such as signaling, localization, or complex assembly, but these alternative mechanisms require further characterization.

    Molecular Glue Degraders and the Expanding Design Space of Drug Discovery · 2026 · DOI

  • The ubiquitination enrichment method captures both monoubiquitinated and polyubiquitinated proteins with broad capture range, but the distinct functional consequences conferred by different ubiquitination states on target proteins remain unclear.

    Degradation of G-quadruplex-binding proteins in chromatin using G4-ligand-based proteolysis-targeting chimeras · 2026 · DOI

  • Future progress will depend on computational modeling of ternary complex formation, improved linker libraries, and translational biomarkers to guide patient selection.

    Emerging Drug Modalities Redefining Small-Molecule Therapeutics: Antibody–Drug Conjugates, Protacs, and Molecular Glues · 2026 · DOI

  • More complex models such as xenografts, patient-derived organoids, and genetically engineered mice need to be incorporated with dynamic molecular profiles to inculcate epigenetics in achieving sustainable clinical response.

    Chromatin Addiction in NUT Carcinoma: Targeted Epigenetic Pharmacology Beyond BET Inhibition · 2026 · DOI

  • We still have a lot to understand about using liquid biopsy in developing epigenetic drugs, particularly for tracking chromatin-state changes and transcriptional reprogramming.

    Chromatin Addiction in NUT Carcinoma: Targeted Epigenetic Pharmacology Beyond BET Inhibition · 2026 · DOI

  • Suppression of epigenetic regulators results in adaptive chromatin remodelling or lineage plasticity, which promotes treatment resistance; identification of compensatory responses and synthetic lethal interactions requires application of functional genomics.

    Chromatin Addiction in NUT Carcinoma: Targeted Epigenetic Pharmacology Beyond BET Inhibition · 2026 · DOI

  • Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanisms by which they affect target ubiquitination remain elusive.

    Mechanism of degrader-targeted protein ubiquitinability · 2024 · DOI

  • Although most cancer drugs modulate the activities of cellular pathways by changing posttranslational modifications (PTMs), little is known regarding the extent and the time- and dose-response characteristics of drug-regulated PTMs.

    Decrypting drug actions and protein modifications by dose- and time-resolved proteomics · 2023 · DOI

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31 open questions have been extracted from the limitations and future-work passages of 155 Protein Degradation and Inhibitors papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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