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

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.

Design and Synthesis of Novel Pyridine-Based Compounds as Potential PIM-1 Kinase Inhibitors, Apoptosis, and Autophagy Inducers Targeting MCF-7 Cell Lines: In Vitro and In Vivo Studies

“…24,25 27 Compound III showed roughly equal activity against the HepG2 cell line as the reference drug in 2023 (IC 50 of 0.0486 M). 28 Compound IV showed the best antiproliferative activities with an IC 50 value of 1.18 μM against MCF-7, better than lapatinib as a reference standard (IC 50 = 4.69 μM). 29 Compounds V and VI were found to be the most active congeners against MCF-7 cells (IC 50 = 0.22 and 1.88 μM after 48 h treatment; 0.11 and 0.80 μM after 72 h treatment, respectively), with increased activity compared to the reference drug doxorubicin (IC 50 = 1.93 μM).…”

“…Moreover, by inhibiting PIM-1 enzymatic activity, 6-(4-(benzyloxy)­phenyl)-4-(4-(dimethylamino)­phenyl)-2-ethoxynicotinonitrile II demonstrated a strong action that drastically decreased PC3 cell reproduction and migration . Compound III showed roughly equal activity against the HepG2 cell line as the reference drug in 2023 (IC 50 of 0.0486 M) . Compound IV showed the best antiproliferative activities with an IC 50 value of 1.18 μM against MCF-7, better than lapatinib as a reference standard (IC 50 = 4.69 μM) .…”

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

“…The study confirmed the significance of oxygen or sulfur substitution at position 2 of the pyridine instead of amino substitution in anticancer and PIM-1 kinase inhibitory activities (Figure 7F). 103 The aforementioned inhibitory structures are derived from quinoline and quinoreoline. It is worth mentioning that 45 was identified using a unique macrocyclization strategy, forming a continuous superhydrophobic surface.…”

“…On the other hand, 50 – 52 not only showcased in vitro inhibitory activity against PIM-2 kinase but also effectively inhibited PIM-1 activity. The study confirmed the significance of oxygen or sulfur substitution at position 2 of the pyridine instead of amino substitution in anticancer and PIM-1 kinase inhibitory activities (Figure F) . The aforementioned inhibitory structures are derived from quinoline and quinoreoline.…”

Anti-proliferative activity of nitroquinolone fused acylhydrazones as non-small cell human lung cancer agents

“…Quinolines are well known for their antimalarial nature and recently their uses have extended further into the disciplines of anti-diabetic agents, 31 anti-cancer therapeutics, 32,33 neurodegenerative diseases 34 etc. The quinoline base exhibits strong binding with various apoptotic proteins, thereby making the heterocycle a good starting point for anti-cancer drug design strategies.…”