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.