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Published on: January 22, 2019
Structural insights of a PI3K/mTOR dual inhibitor with the morpholino-triazine scaffold
Takako Takeda1, Yanli Wang2, Stephen H Bryant1
1National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, 20894, USA.
Abstract:
Stimulation of the PI3K/Akt/mTOR pathway, which controls cell proliferation and growth, is often observed in cancer cell. Inhibiting both PI3K and mTOR in this pathway can switch off Akt activation and hence, plays a powerful role for modulating this pathway. PKI-587, a drug containing the structure of morpholino-triazines, shows a dual and nano-molar inhibition activity and is currently in clinical trial. To provide an insight into the mechanism of this dual inhibition, pharmacophore and QSAR models were developed in this work using compounds based on the morpholino-triazines scaffold, followed by a docking study. Pharmacophore model suggested the mechanism of the inhibition of PI3Kα and mTOR by the compounds were mostly the same, which was supported by the docking study showing similar docking modes. The analysis also suggested the importance of the flat plane shape of the ligands, the space surrounding the ligands in the binding pocket, and the slight difference in the shape of the binding sites between PI3Kα and mTOR.
Insights
Dual inhibition of PI3K and mTOR by morpholino-triazine compounds, like PKI-587, is crucial for cancer therapy. This study reveals their shared inhibition mechanism via pharmacophore and docking, highlighting ligand shape and binding site differences.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Pharmacology
Background:
- The PI3K/Akt/mTOR pathway regulates cell proliferation and growth, and its stimulation is common in cancer.
- Dual inhibition of PI3K and mTOR offers a potent strategy to modulate this pathway by switching off Akt activation.
Purpose of the Study:
- To elucidate the mechanism of dual PI3K and mTOR inhibition by morpholino-triazine-based compounds.
- To provide insights into the drug discovery of novel cancer therapeutics targeting this pathway.
Main Methods:
- Development of pharmacophore and Quantitative Structure-Activity Relationship (QSAR) models.
- In silico molecular docking studies.
- Analysis of morpholino-triazine scaffold compounds.
Main Results:
- Pharmacophore models indicated similar inhibition mechanisms for PI3Kα and mTOR by the studied compounds.
- Docking studies supported these findings, revealing comparable binding modes.
- Ligand shape, binding pocket environment, and subtle differences in PI3Kα and mTOR binding sites are critical for inhibition.
Conclusions:
- The morpholino-triazine scaffold effectively targets both PI3Kα and mTOR through largely conserved mechanisms.
- Understanding these mechanisms aids in designing more potent and selective inhibitors for cancer treatment.
- PKI-587, a promising dual inhibitor, exemplifies the therapeutic potential of this drug class.
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