Discovery of novel small molecules targeting TGF-β signaling for the treatment of non-small cell lung cancer

Acquired resistance to tyrosine kinase inhibitors (TKIs) has become a significant challenge in cancer therapy, underscoring the urgent need for developing alternative therapeutic targets to relieve it. Targeting TGF-β signaling pathway has been emerging as a promising antitumor strategy due to its pivotal role in cancer progression and metastasis. Our previous study identified YR-290 as an anticancer molecule through inhibiting TGF-β signaling, but its poor solubility limited its subsequent development. To addressed the limitations, a new series of YR-290 analogues containing hydrophilic moieties were synthesized and evaluated to improve solubility and potency. The optimal compound 8dc, whose solubility also promoted over 4.7-fold compared to YR-290, showed significant inhibition with IC₅₀ values of 0.05 and 0.09 μM in A549 and NCI–H441, respectively. In addition, 8dc remarkably exhibited anti-NSCLC activities in colony formation, migration and invasion with a concentration-dependent manner in vitro. It also affected cell cycle and induced cell apoptosis in A549 cells. More importantly, 8dc suppressed tumor growth in vivo with minimum toxicity. Mechanism study showed that 8dc exerted anticancer bioactivity by inhibition against TGF-β signaling.