Dual VEGFR-2/PIM-1 kinase inhibition towards surmounting the resistance to antiangiogenic agents via hybrid pyridine and thienopyridine-based scaffolds: Design, synthesis and biological evaluation

Abstract

Angiogenesis is a hallmark in cancer. Most antiangiogenic agents block the action of vascular endothelial growth factor (VEGF). In clinic, patients develop hypoxia-mediated resistance consistent with vascular responses to these agents. Recent studies underlying such resistance revealed hypoxia-inducible PIM-1 kinase upregulation which promotes cancer progression. PIM-1 kinase expression is thus viewed as a new resistance mechanism to antiangiogenic agents. Hence, combining PIM kinase inhibitors with anti-VEGF therapies provides synergistic antitumor response. Inspired by these facts, the current study aims at designing novel dual VEGFR-2/PIM-1 kinase inhibitors via molecular hybridization and repositioning of their pharmacophoric features. Moreover, enhancing the cytotoxic potential of the designed compounds was considered via incorporating moieties mimicking caspase 3/7 activators. Accordingly, series of novel pyridine and thieno[2,3-b]pyridine derivatives were synthesized and screened via MTT assay for cytotoxic activities against normal fibroblasts and four cancer cell lines (HepG-2, Caco-2, MCF-7 and PC-3). Compounds 3a, 9e, 10b and 10c exhibited anticancer activities at nanomolar IC50 with promising safety, activated caspase 3/7 and induced apoptosis as well as DNA fragmentation more than doxorubicin in the four cancer cell lines. Furthermore, they exerted promising dual VEGFR-2/PIM-1 kinase inhibition and significantly exhibited higher therapeutic potential to alter the expression levels of VEGF, p53 and cyclin D than doxorubicin. Interestingly, the most active anticancer compound 10b conferred the highest dual VEGFR-2/PIM-1 kinase inhibition. Finally, their in silico ligand efficiency metrics were acceptable.