Discovery of a new CDK4/6 and PI3K/AKT multiple kinase inhibitor
aminoquinol for the treatment of hepatocellular carcinoma
Background: Hepatocellular carcinoma (HCC) is a lethal malignancy
lacking effective treatment. The Cyclin-dependent kinases 4/6 (CDK4/6)
and PI3K/AKT signal pathways play pivotal roles in carcinogenesis and
are promising therapeutic targets for HCC. Here we identified a new
CDK4/6 and PI3K/AKT multi-kinase inhibitor for the treatment of HCC.
Methods: Using a repurposing and ensemble docking methodology, we
screened a library of worldwide approved drugs to identify candidate
CDK4/6 inhibitors. By MTT, apoptosis, and flow cytometry analysis, we
investigated the effects of candidate drug in reducing
cell-viability，inducing apoptosis, and causing cell-cycle arrest. The
drug combination and thermal proteomic profiling (TPP) method were used
to investigate whether the candidate drug produced antagonistic effect.
The in vivo anti-cancer effect was performed in BALB/C nude mice
subcutaneously xenografted with Huh7 cells. Results: We demonstrated for
the first time that the anti-plasmodium drug aminoquinol is a new CDK4/6
and PI3K/AKT inhibitor. Aminoquinol significantly decreased cell
viability, induced apoptosis, increased the percentage of cells in G1
phase. Drug combination screening indicated that aminoquinol could
produce antagonistic effect with the PI3K inhibitor LY294002. TPP
analysis confirmed that aminoquinol significantly stabilized CDK4, CDK6,
PI3K and AKT proteins. Finally, in vivo study in Huh7 cells xenografted
nude mice demonstrated that aminoquinol exhibited strong anti-tumor
activity, comparable to that of the leading cancer drug 5-fluorouracil
with the combination treatment showed the highest therapeutic effect.
Conclusion: The present study indicates for the first time the discovery
of a new CDK4/6 and PI3K/AKT multi-kinase inhibitor aminoquinol. It
could be used alone or as a combination therapeutic strategy for the
treatment of HCC.