Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway.

Chakrabhavi Dhananjaya Mohan,Sefer Baday,M E Zayed,Kanchugarakoppal S Rangappa,Basappa Basappa,Arunachalam Chinnathambi,Sulaiman Ali Alharbi,Feng Li,Andreas Bender,Shardul Paricharak,Gautam Sethi,Lewis Mervin,Muthu K Shanmugam,Shobith Rangappa,Surender Mohan,V Srinivasa

doi:10.1371/journal.pone.0153155

Abstract

Overactivation of PI3K/Akt/mTOR is linked with carcinogenesis and serves a potential molecular therapeutic target in treatment of various cancers. Herein, we report the synthesis of trisubstituted-imidazoles and identified 2-chloro-3-(4, 5-diphenyl-1H-imidazol-2-yl) pyridine (CIP) as lead cytotoxic agent. Naïve Base classifier model of in silico target prediction revealed that CIP targets RAC-beta serine/threonine-protein kinase which comprises the Akt. Furthermore, CIP downregulated the phosphorylation of Akt, PDK and mTOR proteins and decreased expression of cyclin D1, Bcl-2, survivin, VEGF, procaspase-3 and increased cleavage of PARP. In addition, CIP significantly downregulated the CXCL12 induced motility of breast cancer cells and molecular docking calculations revealed that all compounds bind to Akt2 kinase with high docking scores compared to the library of previously reported Akt2 inhibitors. In summary, we report the synthesis and biological evaluation of imidazoles that induce apoptosis in breast cancer cells by negatively regulating PI3K/Akt/mTOR signaling pathway.

Highlights

Phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is a major signaling cascade which operates downstream to the receptor tyrosine kinases such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and insulin-like growth factor-1 receptor (IGF-1R) [1,2,3]
The relay of signals from the aforementioned growth factor receptors leads to the activation of Phosphoinositide 3-kinase (PI3K) which catalyses the generation of phosphatidylinositol-3,4,5-triphosphate (PIP3) from phosphatidylinositol-4,5-biphosphate [4]
Detailed physical parameters of all the compounds synthesized is provided as supplemental information (S1 Table)

Summary

Introduction

PI3K/Akt/mTOR pathway is a major signaling cascade which operates downstream to the receptor tyrosine kinases such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and insulin-like growth factor-1 receptor (IGF-1R) [1,2,3]. The relay of signals from the aforementioned growth factor receptors leads to the activation of Phosphoinositide 3-kinase (PI3K) which catalyses the generation of phosphatidylinositol-3,4,5-triphosphate (PIP3) from phosphatidylinositol-4,5-biphosphate [4]. PIP3 interacts with pleckstrin homology (PH) domains of phosphoinositide-dependent kinase (PDK) and Akt ( called as Protein Kinase B) and activates them [5]. The PI3K/Akt/mTOR pathway plays a central role in regulation of the cell proliferation, survival, migration, angiogenesis and metabolism and extensively contributes to oncogenesis [8,9,10,11]. Overactivation of PI3K/Akt/mTOR pathway has been reported in many types of cancers offering a unique therapeutic target to design novel heterocycles against malignancies [12,13,14,15]

Methods

Results

Discussion

Conclusion