biostudies-literatureUnknown33(1)Leonardo-Sousa CThe 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 structureMolecular therapy. Oncology200945https://www.ebi.ac.uk/biostudies/studies/S-EPMC11923830biostudies-literatureStructural insights and clinical advances in small-molecule inhibitors targeting TGF-β receptor I.PMC11923830Acurcio RCGuedes RCLeonardo-Sousa CBarriga RFlorindo HFfalseStructural 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 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 structure2025-01-01T00:00:00Z2025 Mar2026-06-02T17:27:01.398Z2025-04-05T22:09:25.701ZS-EPMC119238304011572810.1016/j.omton.2025.200945