Structural insights and clinical advances in small-molecule inhibitors targeting TGF-β receptor I
The dysregulation of the transforming growth factor β (TGF-β) signaling pathway plays a critical role in the onset and progression of several diseases, including cancer. Notably, TGF-β has emerged as a significant barrier to effective outcomes in cancer immunotherapies, particularly those using immu...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
|
| Series: | Molecular Therapy: Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950329925000141 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850236143198535680 |
|---|---|
| author | Carlota Leonardo-Sousa Rodrigo Barriga Helena F. Florindo Rita C. Acúrcio Rita C. Guedes |
| author_facet | Carlota Leonardo-Sousa Rodrigo Barriga Helena F. Florindo Rita C. Acúrcio Rita C. Guedes |
| author_sort | Carlota Leonardo-Sousa |
| collection | DOAJ |
| description | The dysregulation of the transforming growth factor β (TGF-β) signaling pathway plays a critical role in the onset and progression of several diseases, including cancer. Notably, TGF-β has emerged as a significant barrier to effective outcomes in cancer immunotherapies, particularly those using immune checkpoint inhibitors. In response to this challenge, small-molecule inhibitors targeting the TGF-β receptor I (TGF-βRI) have garnered attention as promising candidates for modulating the TGF-β signaling pathway. This comprehensive review focuses on the development of small-molecule inhibitors targeting TGF-βRI. We provide a detailed analysis of the structural biology of TGF-βRI, highlighting key binding interactions and structural insights derived from high-resolution X-ray crystal structures. Additionally, we review the current landscape of TGF-βRI inhibitors in clinical trials, including eight promising inhibitors, and discuss their mechanisms of action, selectivity, and therapeutic potential. Our investigation extends to the patent literature, summarizing over 2 decades of innovation from leading pharmaceutical companies, spanning January 2000–May 2024. This consolidated structural and biochemical knowledge aims to facilitate the design of next-generation TGF-βRI inhibitors, addressing unmet clinical needs in oncology and fibrosis treatment. The synergistic potential of combining TGF-βRI and immune checkpoint inhibitors is also explored, offering promising avenues for enhancing cancer immunotherapy efficacy. |
| format | Article |
| id | doaj-art-32586f4f5bbb40b28290bebf185f4f5a |
| institution | OA Journals |
| issn | 2950-3299 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-32586f4f5bbb40b28290bebf185f4f5a2025-08-20T02:02:01ZengElsevierMolecular Therapy: Oncology2950-32992025-03-0133120094510.1016/j.omton.2025.200945Structural insights and clinical advances in small-molecule inhibitors targeting TGF-β receptor ICarlota Leonardo-Sousa0Rodrigo Barriga1Helena F. Florindo2Rita C. Acúrcio3Rita C. Guedes4Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal; Corresponding author: Helena F. Florindo, Ph.D., Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal.Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal; Corresponding author: Rita C. Acúrcio Ph.D., Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal.Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal; Corresponding author: Rita C. Guedes, Ph.D., Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal.The dysregulation of the transforming growth factor β (TGF-β) signaling pathway plays a critical role in the onset and progression of several diseases, including cancer. Notably, TGF-β has emerged as a significant barrier to effective outcomes in cancer immunotherapies, particularly those using immune checkpoint inhibitors. In response to this challenge, small-molecule inhibitors targeting the TGF-β receptor I (TGF-βRI) have garnered attention as promising candidates for modulating the TGF-β signaling pathway. This comprehensive review focuses on the development of small-molecule inhibitors targeting TGF-βRI. We provide a detailed analysis of the structural biology of TGF-βRI, highlighting key binding interactions and structural insights derived from high-resolution X-ray crystal structures. Additionally, we review the current landscape of TGF-βRI inhibitors in clinical trials, including eight promising inhibitors, and discuss their mechanisms of action, selectivity, and therapeutic potential. Our investigation extends to the patent literature, summarizing over 2 decades of innovation from leading pharmaceutical companies, spanning January 2000–May 2024. This consolidated structural and biochemical knowledge aims to facilitate the design of next-generation TGF-βRI inhibitors, addressing unmet clinical needs in oncology and fibrosis treatment. The synergistic potential of combining TGF-βRI and immune checkpoint inhibitors is also explored, offering promising avenues for enhancing cancer immunotherapy efficacy.http://www.sciencedirect.com/science/article/pii/S2950329925000141MT: Regular Issuetransforming growth factor βTGF-βTGF-β receptor ITGF-βRITGF-βRI inhibitors |
| spellingShingle | Carlota Leonardo-Sousa Rodrigo Barriga Helena F. Florindo Rita C. Acúrcio Rita C. Guedes Structural insights and clinical advances in small-molecule inhibitors targeting TGF-β receptor I Molecular Therapy: Oncology MT: Regular Issue transforming growth factor β TGF-β TGF-β receptor I TGF-βRI TGF-βRI inhibitors |
| title | Structural insights and clinical advances in small-molecule inhibitors targeting TGF-β receptor I |
| title_full | Structural insights and clinical advances in small-molecule inhibitors targeting TGF-β receptor I |
| title_fullStr | Structural insights and clinical advances in small-molecule inhibitors targeting TGF-β receptor I |
| title_full_unstemmed | Structural insights and clinical advances in small-molecule inhibitors targeting TGF-β receptor I |
| title_short | Structural insights and clinical advances in small-molecule inhibitors targeting TGF-β receptor I |
| title_sort | structural insights and clinical advances in small molecule inhibitors targeting tgf β receptor i |
| topic | MT: Regular Issue transforming growth factor β TGF-β TGF-β receptor I TGF-βRI TGF-βRI inhibitors |
| url | http://www.sciencedirect.com/science/article/pii/S2950329925000141 |
| work_keys_str_mv | AT carlotaleonardosousa structuralinsightsandclinicaladvancesinsmallmoleculeinhibitorstargetingtgfbreceptori AT rodrigobarriga structuralinsightsandclinicaladvancesinsmallmoleculeinhibitorstargetingtgfbreceptori AT helenafflorindo structuralinsightsandclinicaladvancesinsmallmoleculeinhibitorstargetingtgfbreceptori AT ritacacurcio structuralinsightsandclinicaladvancesinsmallmoleculeinhibitorstargetingtgfbreceptori AT ritacguedes structuralinsightsandclinicaladvancesinsmallmoleculeinhibitorstargetingtgfbreceptori |