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

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

  • J Enzyme Inhib Med Chem. 2023 Dec;38(1):2152810. doi: 10.1080/14756366.2022.2152810.
Mostafa M M El-Miligy 1,  Marwa E Abdelaziz 1,  Salwa M Fahmy 1,  Tamer M Ibrahim 2,  Marwa M Abu-Serie 3,  Mona A Mahran 1,  Aly A Hazzaa 1
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 3 Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt).
PMID: 36629075 DOI: 10.1080/14756366.2022.2152810
Abstract

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.

Keywords

PIM-1 kinase inhibitors; Pyridine; apoptosis induction; caspase 3/7 activation; quinoline.

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