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Identification and biological evaluation of benzimidazole-based compounds as novel TGFβR1 inhibitors
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DOI：10.1080/14756366.2025.2600746.png)
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Abstract
En 中文
TGF-beta promotes progression and metastasis in later stages of tumour development, and inhibitors targeting TGF-beta or its receptor have faced clinical limitations due to toxicity and poor selectivity. This study aimed to identify novel TGF beta R1 inhibitors by screening the ChemDiv database using a structure-based virtual screening approach. Among the top-ranked compounds, 3282-0487 showed the highest potency. Its analogues were further evaluated, leading to four potent TGF beta R1 inhibitors with sub-micromolar IC50 values. Molecular docking confirmed favourable binding interactions, and structure-activity relationship analysis highlighted key structural features contributing to inhibitory activity. Among these, compound 3282-0486 demonstrated the lowest IC50 values against colorectal cancer cells, inducing apoptosis and dose-dependent anti-migration effects. Its efficacy was further supported by changes in downstream TGF beta R1 signalling, including p-Smad2, EMT markers, and PARP1 cleavage. Additionally, compound 3282-0486 exhibited selectivity for TGF beta R1. Overall, these findings support compound 3282-0486 as a promising TGF beta R1 inhibitor with therapeutic potential.
Keywords:
TGF-beta
TGF beta R1
structure-based virtual screening
kinase selectivity
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