Discovery of new pyridine-quinoline hybrids as competitive and non-competitive PIM-1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities

• Main Authors: Mostafa M. M. El-Miligy (Author), Marwa E. Abdelaziz (Author), Salwa M. Fahmy (Author), Tamer M. Ibrahim (Author), Marwa M. Abu-Serie (Author), Mona A. Mahran (Author), Aly A. Hazzaa (Author)
• Format: Book
• Published: Taylor & Francis Group, 2023-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.1080/14756366.2022.2152810; 1475-6374; 1475-6366
• Keywords: Pyridine; quinoline; apoptosis induction; caspase 3/7 activation; PIM-1 kinase inhibitors; Therapeutics. Pharmacology; RM1-950
• Source: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 38, Iss 1 (2023)

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.