Novel pyridine-based chalcone analogs and triple negative breast cancer: potential therapy & molecular pathways

Triple-negative breast cancer (TNBC) represents one of its most aggressive subtypes, characterized by poor prognosis and resistance to conventional therapies. Given the urgent need for more effective treatment strategies, chalcone derivatives have attracted attention as versatile scaffolds with multitarget anticancer potential. In this study, we evaluated the anticancer efficacy of 14 novel pyridine-based chalcone analogs against TNBC cell lines (MDA-MB-231 and BT-20). Following initial screening, OH17 and OH25 showed promising activity and were selected for further evaluation alongside docetaxel (DTX), a standard chemotherapeutic control. Both OH17 and OH25 significantly reduced TNBC cell viability at low micromolar concentrations. Morphological analysis revealed apoptosis-like features, further supported by cell cycle analysis and Annexin V/PI staining, which demonstrated sub-G1 accumulation and induction of apoptosis. Molecular pathway analysis showed that the compounds upregulated the pro-apoptotic protein BAX while downregulating ERK1/2, with OH17 showing additional EGFR modulation. These effects translated into significant inhibition of cell invasion and colony formation, underscoring their potential to suppress key hallmarks of TNBC aggressiveness. Collectively, our findings highlight OH17 and OH25 as promising chalcone analogs with potent and mechanistically distinct therapeutic activity against TNBC. These results support further preclinical evaluation of pyridine chalcones as next-generation candidates for TNBC therapy.