ArticleCell & bioscience2022
VHL-recruiting PROTAC attenuates renal fibrosis and preserves renal function via simultaneous degradation of Smad3 and stabilization of HIF-2α.
Article in Cell & bioscience, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 19 citations in OpenAlex.
- Beyond hypoxia and ccRCC: the expanding universe of VHL novel targets and next-generation therapeutics.Biomarker research · 2026Review
- Recent advances of dual PROTACs for potential therapeutic applications.Molecular diversity · 2026Review
- Exosomal miR-21-5p from ectopic endometrial stromal cells drives fibrosis progression in endometriosis through direct VHL targeting.Human cell · 2026Article
- PAX3::FOXO1-Targeting PROTAC Induces Myogenic Differentiation of Fusion-Positive Rhabdomyosarcoma Cells.Cancers · 2026Article
- VHL-recruiting PROTAC attenuates AKI-CKD transition via simultaneous degradation of Smad3 and stabilization of HIF-2α.Cell death & disease · 2026Article
- Mechanisms and Design Principles of Proteolysis-Targeting Chimeras and Their Emerging Applications.ACS pharmacology & translational science · 2026Review
- Research progress and future perspectives in proteolysis-targeting chimeras.Frontiers in pharmacology · 2026Review
- Targeting the Undruggable: Recent Progress in PROTAC-Induced Transcription Factor Degradation.Cancers · 2025Review
- Collagen formation, function and role in kidney disease.Nature reviews. Nephrology · 2025Review
- The roles of the ubiquitin-proteasome system in renal disease.International journal of medical sciences · 2025Review
- Article
- Renal tubular epithelial cell quality control mechanisms as therapeutic targets in renal fibrosis.Journal of pharmaceutical analysis · 2024Review
- Review
- Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases.Signal transduction and targeted therapy · 2023Review
- Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances.Journal of translational medicine · 2023Review
- Uncovering the Secrets of Prostate Cancer's Radiotherapy Resistance: Advances in Mechanism Research.Biomedicines · 2023Review
- Review
- PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies.Molecules (Basel, Switzerland) · 2023Review
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
backgroundRenal fibrosis is the pathological foundation of various chronic kidney diseases progressing to end stage renal failure. However, there are currently no nephroprotective drugs targeted to the fibrotic process in clinical practice. Proteolytic targeting chimeras (PROTACs), which reversibly degrade target proteins through the ubiquitin-proteasome pathway, is a novel therapeutic modality. Smad3 is a key pathogenic factor in fibrogenesis while HIF-2α exhibits prominent renal protective effects, which is the natural substrate of von Hippel-Lindau (VHL) E3 Ligase. We hypothesied the construction of VHL-recruiting, Smad3-targeting PROTAC might combine the effects of Smad3 degradation and HIF-2α stabilization, which not only improving the clinical efficacy of PROTAC but also avoiding its potential off-target effects, could greatly improve the possibility of its translation into clinical drugs.
methodsBy joining the Smad3-binding small molecule compound (SMC) to VHL-binding SMC with a linker, we designed and synthesized a Smad3-targeting, VHL-based PROTAC. The effects of this PROTAC on targeted proteins were verified both in vitro and in vivo. The toxicity and pharmacokinetic (PK) evaluations were conducted with both male and female mice. The renal protection effects and mechanism of PROTAC were evaluated in unilateral ureteral obstruction (UUO) and 5/6 subtotal nephrectomy (5/6Nx) mouse model.
resultsBy optimizing the linker and the Smad3-binding SMC, we got a stable and high efficient PROTAC which simultaneously degraded Smad3 and stabilized HIF-2α both in vivo and in vitro. The acute toxicity evaluation showed a pretty large therapeutic window of the PROTAC. The prominent renal protection effects and its underlying mechanism including anti-fibrosis and anti-inflammatory, improving renal anemia and promoting kidney repair, had all been verified in UUO and 5/6Nx mouse model.
conclusionBy accurate combination of PROTAC targeted protein and E3 ligase, we got a Smad3-targeting, VHL-recruting PROTAC which caused Smad3 degradation and HIF-2α stabilization effects simultaneously, and led to the strong renal function protection effects.
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