Bis-thiosemicarbazone derivative as starting agent for synthesis of anti-breast cancer agents and targeting PIM-1 kinase.

AIMS: To design, synthesize, and biologically evaluate novel bis-thiazole derivatives as potential PIM-1 kinase inhibitors for breast cancer therapy.

MATERIALS AND METHODS: A series of new bis-thiazole derivatives were synthesized and evaluated for their antiproliferative activity against MDA-MB-231 and MCF-7 breast cancer cell lines. The most active compound 15c was further investigated for PIM-1 kinase inhibition, selectivity toward normal WI38 cells, apoptosis induction, and molecular interactions with the PIM-1 active site.

RESULTS AND CONCLUSION: Among the synthesized compounds, derivative 15c exhibited the highest antiproliferative activity against MDA-MB-231 and MCF-7 cells, with IC50 values of 2.17 and 1.46 μM, respectively. It demonstrated potent PIM-1 inhibitory activity (IC50 = 0.74 μM), a favorable selectivity index, and low toxicity toward WI38 cells. Furthermore, 15c significantly increased p53 and Bax levels by 6.8- and 6.2-folds, respectively, while reducing Bcl-2 levels to 0.34-fold relative to the control, indicating apoptosis induction. Molecular docking studies revealed strong binding interactions with key amino acid residues within the PIM-1 active site. Hence, compound 15c represents a promising PIM-1 kinase inhibitor with potent antiproliferative and pro-apoptotic activities, supporting its potential as a candidate for breast cancer treatment.