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Computational and in vitro characterization of ICY-5: A potential candidate promoting mitochondrial apoptosis via the
Mesfer Al Shahrani1,2, Meenakshisundaram Balasubramaniam3, Mohammad Y Alshahrani1,2
1Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
Abstract:
Targeted chemotherapy remains the primary choice in controlling various forms of breast cancer (BC) due to its heterogenous gene expressions in various subtypes. In silico and in vitro evaluation of ICY-5, a novel arylidene analogue against c-MET, was performed. ICY-5 exhibited a docking score of -9.6 kcal/mol in inactive conformation and, - 8.6 kcal/mol in active conformation for c-MET. ICY-5 inhibited c-MET enzyme with an IC50 of 34.34 nM. The compound effectively inhibited MDA-MB 231 and MCF-7 cell proliferation, with GI50 values of 62.61 and 75.31 nM, respectively, and hepatocyte growth factor (HGF)/R c-MET phosphorylation with IC50 s of 71.41 and 83.77 nM, respectively. ICY-5 dose-dependently inhibited HGF-induced transmigration, cell scattering, invasion and altered cell cycle. An increase in apoptotic populations of these cells, with a dose-dependent decease in phosphorylation of STAT3 protein was observed. Furthermore, ICY-5 upregulated the caspase-3, caspase-9, Bcl-2-associated X and survivin, and downregulated Bcl-2, vascular endothelial growth factor, matrix metalloproteinase-2 (MMP-2), and MMP-9 in both BC cell lines. In summary, ICY-5 exhibited excellent efficacy in BC cells, targeting c-MET/SAT-3-mediated mitochondrial apoptosis. Further research will be required to ascertain ICY-5 suitability as a targeted chemotherapeutic against multiple forms of BC.
Insights
A novel compound, ICY-5, effectively targets c-MET in breast cancer (BC) cells. It inhibits cell proliferation and induces apoptosis, showing promise as a targeted chemotherapy agent for various BC subtypes.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Breast cancer (BC) exhibits heterogeneous gene expression, necessitating targeted therapies.
- c-MET signaling plays a crucial role in BC progression and survival.
- Developing novel c-MET inhibitors is a key strategy for BC treatment.
Purpose of the Study:
- To evaluate ICY-5, a novel arylidene analogue, as a potential c-MET inhibitor for breast cancer treatment.
- To assess the in silico and in vitro efficacy of ICY-5 against BC cell lines.
- To elucidate the molecular mechanisms underlying ICY-5's anti-cancer effects.
Main Methods:
- In silico molecular docking of ICY-5 against c-MET (inactive and active conformations).
- In vitro enzyme inhibition assays to determine IC50 for c-MET.
- Cell proliferation assays (GI50) and Western blotting to assess signaling pathway modulation (HGF/c-MET, STAT3, apoptosis markers).
- Transmigration, cell scattering, and cell cycle assays were performed.
Main Results:
- ICY-5 demonstrated strong binding affinity to c-MET in silico.
- ICY-5 potently inhibited c-MET enzyme activity (IC50 = 34.34 nM) and proliferation of MDA-MB 231 and MCF-7 cells (GI50 = 62.61 and 75.31 nM).
- ICY-5 suppressed HGF-induced c-MET phosphorylation, cell migration, invasion, and induced apoptosis, modulating key proteins (STAT3, caspase-3, -9, Bcl-2 family, survivin, VEGF, MMP-2, MMP-9).
Conclusions:
- ICY-5 exhibits significant anti-cancer efficacy in breast cancer cells by targeting the c-MET/STAT3 pathway and inducing mitochondrial apoptosis.
- The compound demonstrates potential as a targeted chemotherapeutic agent for multiple breast cancer subtypes.
- Further investigation is warranted to confirm ICY-5's clinical applicability in breast cancer therapy.
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