Abstract
The aberrant activation of the PI3K/mTOR signaling pathway is implicated in various human cancers. Thus, the development of inhibitors targeting mTOR has attracted considerable attention. In this study, we used a structure-based drug design strategy to discover a highly potent and kinase-selective mTOR inhibitor 24 (PT-88), which demonstrated an mTOR inhibitory IC50 value of 1.2 nM without obvious inhibition against another 195 kinases from the kinase profiling screening. PT-88 displayed selective inhibition against MCF-7 cells (IC50: 0.74 μM) with high biosafety against normal cells, in which autophagy induced by mTOR inhibition was implicated. After successful encapsulation in a lipodisc formulation, PT-88 demonstrated favorable pharmacokinetic and biosafety profiles and exerted a large antitumor effect in an MCF-7 subcutaneous bearing nude mice model. Our study shows the discovery of a highly selective mTOR inhibitor using a structure-based drug discovery strategy and provides a promising antitumor candidate for future study and development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents* / chemical synthesis
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Antineoplastic Agents* / chemistry
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Antineoplastic Agents* / pharmacology
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Antineoplastic Agents* / therapeutic use
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Autophagy / drug effects
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Breast Neoplasms* / drug therapy
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Breast Neoplasms* / pathology
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Cell Proliferation / drug effects
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Drug Design*
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Female
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Humans
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MCF-7 Cells
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MTOR Inhibitors* / chemical synthesis
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MTOR Inhibitors* / chemistry
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MTOR Inhibitors* / pharmacology
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MTOR Inhibitors* / therapeutic use
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Mice
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Mice, Inbred BALB C
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Mice, Nude*
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Structure-Activity Relationship
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TOR Serine-Threonine Kinases* / antagonists & inhibitors
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TOR Serine-Threonine Kinases* / metabolism
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Triazines* / chemical synthesis
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Triazines* / chemistry
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Triazines* / pharmacokinetics
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Triazines* / pharmacology
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Triazines* / therapeutic use
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Xenograft Model Antitumor Assays
Substances
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Triazines
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TOR Serine-Threonine Kinases
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Antineoplastic Agents
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MTOR Inhibitors
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MTOR protein, human
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Protein Kinase Inhibitors