Development of novel cyanopyridines as PIM-1 kinase inhibitors with potent anti-prostate cancer activity: Synthesis, biological evaluation, nanoparticles formulation and molecular dynamics simulation.

[Display omitted] • 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 IC 50 = 0.248, 0.13, 0.326 and 0.245 μM, respectively. The most powerful derivatives 2b , 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. [ABSTRACT FROM AUTHOR]