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 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.