Novel cancer chemotherapy hits by molecular topology: dual Akt and Beta-catenin inhibitors

Abstract

Background and purpose: Colorectal and prostate cancers are two of the most common types and cause of a high rate of deaths worldwide. Therefore, any strategy to stop or at least slacken the development and progression of malignant cells is an important therapeutic choice. The aim of the present work is the identification of novel cancer chemotherapy agents. Nowadays, many different drug discovery approaches are available, but this paper focuses on Molecular Topology, which has already demonstrated its extraordinary efficacy in this field, particularly in the identification of new hit and lead compounds against cancer. This methodology uses the graph theoretical formalism to numerically characterize molecular structures through the so called topological indices. Once obtained a specific framework, it allows the construction of complex mathematical models that can be used to predict physical, chemical or biological properties of compounds. In addition, Molecular Topology is highly efficient in selecting and designing new hit and lead drugs. According to the aforementioned, Molecular Topology has been applied here for the construction of specific Akt/mTOR and β-catenin inhibition mathematical models in order to identify and select novel antitumor agents.

Experimental approach: Based on the results obtained by the selected mathematical models, six novel potential inhibitors of the Akt/mTOR and β-catenin pathways were identified. These compounds were then tested in vitro to confirm their biological activity.

Conclusion and implications: Five of the selected compounds, CAS n° 256378-54-8 (Inhibitor n°1), 663203-38-1 (Inhibitor n°2), 247079-73-8 (Inhibitor n°3), 689769-86-6 (Inhibitor n°4) and 431925-096 (Inhibitor n°6) gave positive responses and resulted to be active for Akt/mTOR and/or β-catenin inhibition. This study confirms once again the Molecular Topology's reliability and efficacy to find out novel drugs in the field of cancer.

Fig 1. PI3K/Akt/mTOR pathway related to cancer onset and progression [11].

Fig 2. Scheme of Akt and β-catenin inhibitors research through Molecular Topology by virtual screening on SPECS databases.

Fig 3. Pharmacological distribution diagram for natural Akt inhibitors obtained using the DF₁ (the black colour represents Akt inhibitors and the white colour, the compounds without Akt inhibition activity).

Fig 4. Pharmacological distribution diagram for Akt inhibitors obtained using the DF₂ (the black colour represents Akt inhibitors and the white colour, the compounds without Akt inhibition activity).

Fig 5. Pharmacological distribution diagram for natural β-catenin inhibitors obtained using the DF₃ (the black color represents natural β-catenin inhibitors and the white color, the compounds without β-catenin inhibition activity).

Fig 6. Pharmacological distribution diagram for β-catenin inhibitors obtained using the DF₄ (the black color represents β-catenin inhibitors and the white color, the compounds without β-catenin inhibition activity).

Fig 7. Effect of of selected anti-cancer agents on Akt/mTOR signaling pathway.

PC-3 cells were treated with vehicle (C) or 50 μM of the selected compounds and proteins were detected by Western blot. Upper panel, a representative image of three different experiments. Lower panel, densitometric values represented as the mean ± S.D. of the three experiments.

Fig 8. Effect of selected anti-cancer agents on β-Catenin/CyclinD1 signaling pathway.

PC-3 cells were treated with vehicle (C) or 50 μM of the selected compounds and proteins were detected by Western blot. Upper panel, a representative image of three different experiments. Lower panel, densitometric values represented as the mean ± S.D. of the three experiments.

Fig 9. Effect of selected anti-cancer agents on β-catenin cellular distribution in PC-3 cells.

PC-3 cells were seeded on glass coverslips and pre-treated for 30 min with 50 μM of the inhibitors and then co-treated with 40 ng/ml Wnt3 (Wnt) for 4 h. Cells were stained with polyclonal antibody anti-beta-catenin followed by Alexa-Fluor488-conjugated anti rabbit IgG as described in methods. Confocal image shown is representative of two experiments.

Fig 10. Cancer chemotherapeutic agents selected by Molecular Topology.