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New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds 5b, 5c, 6e, 13a, 13c, and 14a showed in-vitro low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent in-vitro anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, 6e, 13a, and 13c significantly induced apoptosis with percentage more than 66%. Moreover, 6e, 13a, and 13c significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 5c, 6e, and 14a showed potent in-vitro PIM-1 kinase inhibitory activity. While, 5b showed potent in-vitro PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver–Burk double-reciprocal plot indicated that 5b, 5c, 6e, and 14a behaved as competitive inhibitors while 13a behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, in-silico affinity came in coherence with the observed in-vitro inhibitory activities against PIM-1/2 kinases. [ABSTRACT FROM AUTHOR]

A series of 36 pyrazol-4-yl pyridine derivatives (8a-i , 9a-i , 10a-i , and 11a-i) was designed, synthesized, and evaluated for its antiproliferative activity over NCI-60 cancer cell line panel and inhibitory effect against JNK isoforms (JNK1, JNK2, and JNK3). All the synthesized compounds were tested against the NCI-60 cancer cell line panel. Compounds 11b , 11c , 11g , and 11i were selected to determine their GI 50s and exerted a superior potency over the reference standard SP600125 against the tested cell lines. 11c showed a GI 50 of 1.28 μM against K562 leukemic cells. Vero cells were used to assess 11c cytotoxicity compared to the tested cancer cells. The target compounds were tested against h JNK isoforms in which compound 11e exhibited the highest potency against JNK isoforms with IC 50 values of 1.81, 12.7, and 10.5 nM against JNK1, JNK2, and JNK3, respectively. Kinase profiling of 11e showed higher JNK selectivity in 50 kinase panels. Compounds 11c and 11e showed cell population arrest at the G2/M phase, induced early apoptosis, and slightly inhibited beclin-1 production at higher concentrations in K562 leukemia cells relative to SP600125. NanoBRET assay of 11e showed intracellular JNK1 inhibition with an IC 50 of 2.81 μM. Also, it inhibited CYP2D6 and 3A4 with different extent and its hERG activity showed little cardiac toxicity with an IC 50 of 4.82 μM. h JNK3 was used as a template to generate the h JNK1 crystal structure to explore the binding mode of 11e (PDB ID: 8ENJ) with a resolution of 2.8 °A and showed a typical type I kinase inhibition against h JNK1. Binding energy scores showed that selectivity of 11e towards JNK1 could be attributed to additional hydrophobic interactions relative to JNK3. [Display omitted] • Compounds 11c exhibited GI 50 of 1.28 μM against NCI K562 cells. • Compound 11e showed some selectivity towards JNK1 with IC 50 of 1.81 nM at 1 μM ATP and showed high JNK selectivity among 50 kinases. • 11c and 11e exhibited G2/M phase arrest, early apoptosis and slight beclin-1 inhibition against K562 cells in comparison with SP600125. • 11e inhibited JNK1 in HEK293 cells, CYP2A6, and CYP3A4 and showed little hERG activity. • 11e showed type I kinase inhibition upon co-crystallization with JNK isoforms (PDB: 8ENJ). [ABSTRACT FROM AUTHOR]