Identification and biological evaluation of benzimidazole-based compounds as novel TGFβR1 inhibitors

TGF-β promotes progression and metastasis in later stages of tumour development, and inhibitors targeting TGF-β or its receptor have faced clinical limitations due to toxicity and poor selectivity. This study aimed to identify novel TGFβR1 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 TGFβR1 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 TGFβR1 signalling, including p-Smad2, EMT markers, and PARP1 cleavage. Additionally, compound 3282-0486 exhibited selectivity for TGFβR1. Overall, these findings support compound 3282-0486 as a promising TGFβR1 inhibitor with therapeutic potential.