Academic Journal
Novel VHL ligand-based PROTACs targeting JNK1: design, synthesis, and biological evaluation with potent anti-EMT activity.
| Τίτλος: | Novel VHL ligand-based PROTACs targeting JNK1: design, synthesis, and biological evaluation with potent anti-EMT activity. |
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| Συγγραφείς: | Ren S; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China., Zhang Y; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China., Hao R; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China., Yuan J; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China., Chi M; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China., Cai W; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China., Gu W; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China., Huang Y; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China., Yuan Y; Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, TX 78229, USA., Chen X; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Element Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. Electronic address: xch226@hznu.edu.cn., Ma L; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: malei@ecust.edu.cn. |
| Πηγή: | Bioorganic chemistry [Bioorg Chem] 2026 Oct 05; Vol. 181, pp. 110388. Date of Electronic Publication: 2026 Aug 15. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Amsterdam : Elsevier Original Publication: New York, London, Academic Press. |
| Ιατρικοί όροι (MeSH): | Epithelial-Mesenchymal Transition*/drug effects , Von Hippel-Lindau Tumor Suppressor Protein*/metabolism , Mitogen-Activated Protein Kinase 8*/metabolism , Mitogen-Activated Protein Kinase 8*/antagonists & inhibitors , Drug Design*, Indazoles/pharmacology ; Indazoles/chemical synthesis ; Indazoles/chemistry ; Humans ; Proteolysis Targeting Chimera ; Ligands ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug |
| Περίληψη: | Epithelial-mesenchymal transition (EMT) is essential for embryogenesis and tissue regeneration, yet its aberrant activation is closely associated with organ fibrosis and tumor metastasis. c-Jun N-terminal kinase 1 (JNK1) has been identified as a key mediator of transforming growth factor-β (TGF-β)-driven EMT, making it a promising therapeutic target. Herein, we describe the design, synthesis, and biological evaluation of a series of JNK1-targeting PROTACs that recruit either CRBN or VHL E3 ligases. Systematic structure-activity relationship optimization led to the discovery of compound YC2, which incorporates a newly developed VHL ligand modified with a 2,4-dimethyloxazole moiety, as a potent and selective degrader. YC2 induced efficient, concentration- and time-dependent degradation of JNK1 (DC₅₀ of 4.90 nM) via VHL-mediated ubiquitin-proteasome pathway engagement, while displaying strong selectivity over related kinases including JNK2, p38α, and ERK. Moreover, YC2 markedly attenuated TGF-β1-induced EMT, as evidenced by reduced fibronectin levels and restoration of E-cadherin expression, with efficacy comparable to nintedanib. Collectively, YC2 featuring a novel VHL ligand demonstrates excellent degradation potency and selectivity for JNK1, highlighting its potential as a valuable chemical probe for EMT-associated pathologies. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Epithelial-mesenchymal transition; JNK1; PROTAC; VHL E3 ligase |
| Substance Nomenclature: | 0 (Proteolysis Targeting Chimera) 0 (Ligands) EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein) EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8) EC 6.3.2.- (VHL protein, human) 154453-18-6 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole) 0 (Indazoles) |
| Entry Date(s): | Date Created: 20260818 Date Completed: 20260909 Latest Revision: 20260909 |
| Update Code: | 20260909 |
| DOI: | 10.1016/j.bioorg.2026.110388 |
| PMID: | 42612267 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1090-2120 |
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| DOI: | 10.1016/j.bioorg.2026.110388 |