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Design, Synthesis, Formulation, and Bioevaluation of Trisubstituted Triazines as Highly Selective mTOR Inhibitors for
Qiwen Sun1, Yuxiu Chu2, Nana Zhang1
1Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang 561113, P. R. China.
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.
Insights
Researchers discovered PT-88, a potent and selective mTOR inhibitor, using structure-based drug design. This compound shows promise as an anti-cancer therapeutic with favorable safety and efficacy in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Aberrant PI3K/mTOR signaling is a hallmark of many human cancers.
- Targeting mTOR is a key strategy for cancer therapy development.
Purpose of the Study:
- To discover a highly potent and kinase-selective mTOR inhibitor using structure-based drug design.
- To evaluate the anti-tumor efficacy and safety of the novel inhibitor PT-88.
Main Methods:
- Structure-based drug design was employed to identify mTOR inhibitor 24 (PT-88).
- Kinase profiling was performed against 195 kinases.
- Cellular assays (MCF-7) and in vivo studies in a mouse model were conducted.
Main Results:
- PT-88 demonstrated potent mTOR inhibition (IC50: 1.2 nM) with high selectivity.
- Selective inhibition of MCF-7 cancer cells (IC50: 0.74 μM) with good biosafety against normal cells.
- Lipodisc-encapsulated PT-88 showed favorable pharmacokinetics, biosafety, and significant anti-tumor effects in vivo.
Conclusions:
- A highly selective mTOR inhibitor, PT-88, was successfully discovered via structure-based drug design.
- PT-88 exhibits potent anti-cancer activity and a promising safety profile, warranting further development.
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