Design, Synthesis, Formulation, and Bioevaluation of Trisubstituted Triazines as Highly Selective mTOR Inhibitors for the Treatment of Human Breast Cancer

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.