Academic Journal
Design, synthesis, and biological evaluation of ALK5 PROTAC degraders for pulmonary fibrosis.
| Τίτλος: | Design, synthesis, and biological evaluation of ALK5 PROTAC degraders for pulmonary fibrosis. |
|---|---|
| Συγγραφείς: | Yue L; Department of High Altitude Medicine, Center for High Altitude Medicine, Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Li Y; Department of High Altitude Medicine, Center for High Altitude Medicine, Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Gan C; Department of High Altitude Medicine, Center for High Altitude Medicine, Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: gancailing@scu.edu.cn., Sun M; Department of High Altitude Medicine, Center for High Altitude Medicine, Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Deng C; Department of High Altitude Medicine, Center for High Altitude Medicine, Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Xue T; Department of High Altitude Medicine, Center for High Altitude Medicine, Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Xie Y; Department of High Altitude Medicine, Center for High Altitude Medicine, Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Liu H; Department of High Altitude Medicine, Center for High Altitude Medicine, Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Liu Z; Department of High Altitude Medicine, Center for High Altitude Medicine, Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: liuzhihao@scu.edu.cn., Ye T; Department of High Altitude Medicine, Center for High Altitude Medicine, Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Institute of High Altitude Medicine, High Altitude Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Xi Zang Hospital of West China Hospital, Sichuan University, Lhasa, Xizang, 850000, China. Electronic address: yeth1309@scu.edu.cn. |
| Πηγή: | Bioorganic chemistry [Bioorg Chem] 2026 Aug 15; Vol. 178, pp. 109945. Date of Electronic Publication: 2026 May 06. |
| 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): | Pulmonary Fibrosis*/drug therapy , Pulmonary Fibrosis*/metabolism , Pulmonary Fibrosis*/pathology , Receptor, Transforming Growth Factor-beta Type I*/antagonists & inhibitors , Receptor, Transforming Growth Factor-beta Type I*/metabolism , Protein Kinase Inhibitors*/chemical synthesis , Protein Kinase Inhibitors*/pharmacology , Protein Kinase Inhibitors*/chemistry , Drug Design*, Proteolysis/drug effects ; Animals ; Mice ; Proteolysis Targeting Chimera ; NIH 3T3 Cells ; Humans ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug |
| Περίληψη: | Pulmonary fibrosis (PF) is a progressive and fatal lung disease characterized by excessive extracellular matrix (ECM) deposition, leading to irreversible scarring and respiratory failure. With limited treatment options, there is an urgent need for novel therapeutic strategies. Activin receptor-like kinase 5 (ALK5), a type I receptor serine/threonine kinase, serves as the principal mediator of transforming growth factor-β (TGF-β) signaling and a pivotal driver of PF pathogenesis. Given the central role of ALK5 in fibrogenesis, targeting ALK5 represents a promising therapeutic approach. Conventional ALK5 inhibitors primarily target kinase activity, whereas proteolysis-targeting chimeras (PROTACs) may offer a promising therapeutic strategy by inducing degradation of the target protein. Herein, we report the discovery of a series of novel ALK5-targeting PROTAC degraders. The lead compound, A31, induced ALK5 degradation in NIH3T3 cells and demonstrated inhibition of ALK5 downstream signaling and fibroblast activation. Furthermore, A31 exhibits favorable pharmacokinetics following intraperitoneal administration, in vivo anti-fibrotic efficacy, and no significant toxicity at efficacious doses. Collectively, our study supports the feasibility of ALK5-targeting degradation as a potential therapeutic strategy for pulmonary fibrosis and highlights the therapeutic potential of PROTAC-based strategies in fibrotic diseases. (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: A31; ALK5; PROTAC; Pulmonary fibrosis; TGF-β |
| Substance Nomenclature: | EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type I) 0 (Proteolysis Targeting Chimera) 0 (Protein Kinase Inhibitors) EC 2.7.11.30 (TGFBR1 protein, human) |
| Entry Date(s): | Date Created: 20260513 Date Completed: 20260716 Latest Revision: 20260716 |
| Update Code: | 20260717 |
| DOI: | 10.1016/j.bioorg.2026.109945 |
| PMID: | 42127739 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1090-2120 |
|---|---|
| DOI: | 10.1016/j.bioorg.2026.109945 |