Discovering new mTOR inhibitors for cancer treatment through virtual screening methods and in vitro assays.

Ling Wang,Xian-Hui He,Miao Yu,Yong-Sheng Lin,Qiong Gu,Li-Hui Xu,Bao Cheng,Jun Xu,Lei Chen

doi:10.1038/srep18987

Abstract

Mammalian target of rapamycin (mTOR) is an attractive target for new anticancer drug development. We recently developed in silico models to distinguish mTOR inhibitors and non-inhibitors. In this study, we developed an integrated strategy for identifying new mTOR inhibitors using cascaded in silico screening models. With this strategy, fifteen new mTOR kinase inhibitors including four compounds with IC50 values below 10 μM were discovered. In particular, compound 17 exhibited potent anticancer activities against four tumor cell lines, including MCF-7, HeLa, MGC-803, and C6, with IC50 values of 1.90, 2.74, 3.50 and 11.05 μM. Furthermore, cellular studies and western blot analyses revealed that 17 induces cell death via apoptosis by targeting both mTORC1 and mTORC2 within cells and arrests the cell cycle of HeLa at the G1/G0-phase. Finally, multi-nanosecond explicit solvent simulations and MM/GBSA analyses were carried out to study the inhibitory mechanisms of 13, 17, and 40 for mTOR. The potent compounds presented here are worthy of further investigation.

Highlights

Mammalian target of rapamycin is an attractive target for new anticancer drug development
The mammalian target of rapamycin plays a critical role in several signaling pathways, controlling cell growth, proliferation, angiogenesis, protein translation, energy homeostasis, and lipid metabolism1,2. mTOR exists in two complexes: mTOR complex 1 and complex 2
The mTOR complex 1 (mTORC1) consists of Raptor, LST8, PRAS40 and Deptor and, regulates protein synthesis through the phosphorylation of p70S6K1 and 4E-BP13

Summary

Introduction

Mammalian target of rapamycin (mTOR) is an attractive target for new anticancer drug development. An integrated virtual screening strategy using combining multiple classification models with molecular docking approach was employed to discover new ATP-competitive mTOR inhibitors (Fig. 1). The hits selected via virtual screening were validated using an in vitro mTOR kinase assay.

Results

Conclusion