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Keywords = Medicinal Chemistry Strategies in Targeting TGF-βR1 Kinase Domain

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21 pages, 4294 KB  
Review
Medicinal Chemistry Strategies in Targeting TGF-βR1 Kinase Domain: Unveiling Insights into Inhibitor Structure–Activity Relationship (SAR)
by Nusaiba A. Babiker, Soam Nadeem, Hasan Abu Kariem, Afra Abdul Hameed, Ahmed T. Negmeldin and Eman M. El-labbad
Pharmaceuticals 2025, 18(5), 716; https://doi.org/10.3390/ph18050716 - 13 May 2025
Cited by 5 | Viewed by 4437
Abstract
The transforming growth factor-β (TGF-β) signaling pathway is involved in various cellular functions, including immunological response, extracellular matrix formation, differentiation, growth and development, and cell cycle regulation. The TGF β receptor type 1 (TGF-βR1) has emerged as a key component of this pathway, [...] Read more.
The transforming growth factor-β (TGF-β) signaling pathway is involved in various cellular functions, including immunological response, extracellular matrix formation, differentiation, growth and development, and cell cycle regulation. The TGF β receptor type 1 (TGF-βR1) has emerged as a key component of this pathway, exhibiting significant overexpression in diverse malignancies, including hepatocellular carcinoma, gastric cancer, breast cancer, and colon cancer. Multiple therapeutic targets have been identified for the TGF-β signaling pathway, encompassing antibodies, ligand traps, vaccines, antisense oligonucleotides, and small-molecule TGF-βR1 kinase inhibitors. This review delineates the structural and functional characteristics of the small-molecule TGF-βR1 kinase inhibitors. The inhibitors discussed herein are categorized based on shared pharmacophoric features, notably a five-membered heterocyclic ring linked to three distinct features (R1, R2, and R3). These features interact with amino acids within the selectivity pocket, hinge region, or solvent-exposed area, respectively. These insights contribute to a clearer understanding of the structural requirements for selective TGF-βR1 inhibition. The presented findings in this review article offer a valuable foundation for future drug discovery efforts targeting the TGF-β signaling pathway. Full article
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