The structure-activity relationship study of torkinib derivatives as mTOR inhibitors with senolytic and STAT3 inhibitory activities.

The mechanistic target of rapamycin (mTOR) sits at the center of several cellular pathways determining cell growth, function, and stress adaptation. Dysregulated mTOR signaling contributes to aging-related diseases and cancer, making mTOR inhibitors an important class of anticancer therapeutics. Likewise, STAT3 is a transcription factor that drives cell proliferation and survival, and its hyperactivation is implicated in many cancers. As a result, STAT3 inhibitors also represent a promising group of anticancer compounds. This study describes the synthesis and characterization of 10 heteroarene derivatives of torkinib, a known mTOR inhibitor. We evaluated these compounds for their mTOR and STAT3 inhibitory activities, growth inhibitory and senolytic effects. A structure-activity relationship (SAR) study and molecular docking analysis were conducted to elucidate key structural features. Notably, torkinib derivative 4k demonstrated potent mTOR inhibition without affecting STAT3 phosphorylation, whereas its analog 4j inhibited phosphorylation of both mTOR and STAT3. Furthermore, compared to compound 4j, compound 4k exhibited cytotoxicity against both proliferating and senescent cells, comparable to torkinib despite its weaker TORC1 inhibition. In conclusion, our findings reveal structural alignments crucial for enhanced mTOR and STAT3 inhibition.