Design, synthesis and docking study of pyridine and thieno[2,3-b] pyridine derivatives as anticancer PIM-1 kinase inhibitors

Abstract

A series of pyridine and thieno[2,3-b]pyridine derivatives have been designed and synthesized as anticancer PIM-1 kinase inhibitors. Thirty-seven compounds were selected by NCI to be tested initially at a single dose (10 µM) in the full NCI 60 cell line panel. Compound 5b showed potent anticancer activity and was tested twice in the five-dose assay which confirmed its potent antitumor activity (GI₅₀ values 0.302-3.57 µM) against all tested tumor cell lines except six cell lines where they showed moderate sensitivity. This compound was sent to NCI biological evaluation committee and still under consideration for further testing. In addition, the most active anticancer compounds in each series, 5b, 8d, 10c, 13h, and 15e, were evaluated for their PIM-1 kinase inhibitory activity. Compound 8d was the most potent one with IC₅₀ = 0.019 µM followed by 5b, 15e, 10c and 13h with IC₅₀ values 0.044, 0.083, 0.128 and 0.479 µM respectively. Moreover, docking study of the most active compounds in PIM-1 kinase active site was consistent with the in vitro activity.

Keywords: Anticancer; PIM-1 kinase inhibitors; Pyridine; Thieno[2,3-b]pyridine.