Abstract
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•A new series of 3-cyanopyridines were synthesized as PIM-1 kinase inhibitors.•Anti-tumor activity was assessed against PC-3 and DU-145 prostate cancer cell lines.•Compounds 2b, 3b, 4b, and 5b revealed high potency and high safety profiles.•Nanoparticles formulation of compound 3b was prepared that improved the activity.•Molecular docking and dynamic simulation was done in the PIM-1 active site.
Recently, inhibition of PIM-1 enzyme is found as an effective route in the fight against proliferation of cancer. Herein, new cyano pyridines that target PIM-1 kinase were designed, synthesized, and biologically evaluated. Two prostate cell lines were used to examine each of the new compounds in vitro for anticancer activity, namely, PC-3 and DU-145. The cyanopyridine derivatives 2b, 3b, 4b, and 5b with an N,N-dimethyl phenyl group at the pyridine ring's 4-position showed considerable antitumor effect on the tested cell lines. Additionally, the high selectivity index revealed that these compounds were less cytotoxic to normal WI-38 cells. Furthermore, they exhibited strong inhibitory effect on PIM-1 having IC50 = 0.248, 0.13, 0.326 and 0.245 μM, respectively. The most powerful derivatives2b, 3b, 4b, and 5b, were chosen for further examination of their inhibitory potential on both kinases (PIM-2 and PIM-3). Interestingly, upon loading compound 3b in a cubosomes formulation with nanometric size, improvements in cytotoxicity and inhibitory effect on PIM-1 kinase were observed. In silico ADME parameters study revealed that compound 3b is orally bioavailable without penetration to the blood-brain barrier. Further, the docking simulations revealed the ability of our potent compounds to well accommodate the PIM-1 kinase active site forming stable complexes. In a 150 ns MD simulation, the most powerful PIM-1 inhibitor 3b produced stable complex with the PIM-1 enzyme (RMSD = 1.76). Furthermore, the 3b–PIM-1 complex has the low binding free energy (−242.2 kJ/mol) according to the MM-PBSA calculations.