Discovery and mechanistic insights of novel Piperlongumine analogs as potent Bcr-Abl kinase inhibitors.

In the exploration and discovery of potential anticancer candidates with novel mechanisms of action, a series of novel piperlongumine (PL) analogs was designed and synthesized. The majority of compounds demonstrated significant anti-proliferative effects in vitro, particularly with the 2-Cl analogs C1-C16. Notably, compound C5 exhibited the most potent anti-proliferative activity against K562 cells (IC = 0.11 μM). Inspiringly, C5 was also found to selectively enhance the accumulation of ROS and induce apoptosis. Transcriptomic analysis revealed that the differentially expressed genes (DEGs) primarily encompassed apoptotic, PI3K/AKT signaling pathways, and other associated information. Molecular docking results revealed that C5 exhibited robust hydrogen bond interactions with specific amino acid residues in the Imatinib-Bcr-Abl and Ponatinib-Bcr-Abl protein kinase models, suggesting a plausible binding model based on the docking scores. The findings suggest that C5 exhibits promising potential as a highly efficacious for an anti-leukemia agent, thereby providing a valuable avenue for further exploration and application.