Structure optimization at position five of 4-thiazolidinone resulted in new potent PIM1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities for combating colorectal cancer

Abstract

New thymol – 5-phenylthiazolidin-4-one hybrids were synthesized aiming to interact with the lipophilic flexible p-loop of PIM kinase active site via induced-fit binding mode to increase affinity hence anticancer activity against colorectal cancer (CRC). All target compounds were screened for their cytotoxicity against normal human lung fibroblasts and anticancer activity against CRC Caco-2 cell lines. 6c and 6e exhibited the highest anticancer activity at doses less than their EC₁₀₀ on normal human cells. In addition, 6c and 6e were further tested against liver cancer cell line (HepG-2) and breast cancer cell line (MCF-7) and proved their potent anticancer activities. Furthermore, both induced apoptosis in Caco-2 cell lines by 39 and 55 % and enhanced caspase 3/7 activation by 43 and 65 %, respectively. Besides, 6c and 6e revealed in vitro inhibitory activity against PIM1 kinase more than PIM2 kinase. Furthermore, induced fit docking and molecular dynamics simulation of 6c and 6e predicted enhanced PIM1 kinase activity via interaction to flexible p-loop. Moreover, both could act as PIM1 kinase competitive non-ATP mimetics as they interacted with Lys67.