10 research outputs found
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
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
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
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
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
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
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
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
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
Phospholipid Type Regulates Protein Corona Composition and <i>In Vivo</i> Performance of Lipid Nanodiscs
Over
the years, there has been significant interest in PEGylated
lipid-based nanocarriers within the drug delivery field. The inevitable
interplay between the nanocarriers and plasma protein plays a pivotal
role in their in vivo biological fate. Understanding
the factors influencing lipid-based nanocarrier and protein corona
interactions is of paramount importance in the design and clinical
translation of these nanocarriers. Herein, discoid-shaped lipid nanodiscs
(sNDs) composed of different phospholipids with varied lipid tails
and head groups were fabricated. We investigated the impact of phospholipid
components on the interaction between sNDs and serum proteins, particle
stability, and biodistribution. The results showed that all of these
lipid nanodiscs remained stable over a 15 day storage period, while
their stability in the blood serum demonstrated significant differences.
The sND composed of POPG exhibited the least stability due to its
potent complement activation capability, resulting in rapid blood
clearance. Furthermore, a negative correlation between the complement
activation capability and serum stability was identified. Pharmacokinetic
and biodistribution experiments indicated that phospholipid composition
did not influence the capability of sNDs to evade the accelerated
blood clearance phenomenon. Complement deposition on the sND was inversely
associated with the area under the curve. Additionally, all lipid
nanodiscs exhibited dominant adsorption of apolipoprotein. Remarkably,
the POPC-based lipid nanodisc displayed a significantly higher deposition
of apolipoprotein E, contributing to an obvious brain distribution,
which provides a promising tool for brain-targeted drug delivery