10.1371/journal.pone.0153155 Chakrabhavi Dhananjaya Mohan Chakrabhavi Dhananjaya Mohan V. Srinivasa V. Srinivasa Shobith Rangappa Shobith Rangappa Lewis Mervin Lewis Mervin Surender Mohan Surender Mohan Shardul Paricharak Shardul Paricharak Sefer Baday Sefer Baday Feng Li Feng Li Muthu K. Shanmugam Muthu K. Shanmugam Arunachalam Chinnathambi Arunachalam Chinnathambi M. E. Zayed M. E. Zayed Sulaiman Ali Alharbi Sulaiman Ali Alharbi Andreas Bender Andreas Bender Gautam Sethi Gautam Sethi Basappa Basappa Kanchugarakoppal S. Rangappa Kanchugarakoppal S. Rangappa Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway Public Library of Science 2016 PARP Human Breast Cancer Cells Akt 2 kinase Na ïve Base classifier model breast cancer cells downregulated CXCL Akt 2 inhibitors silico target prediction VEGF PDK Oncogenic PI 3K Signaling Pathway Overactivation PI 3K synthesis CIP docking 2016-04-20 05:25:55 Dataset https://plos.figshare.com/articles/dataset/Trisubstituted_Imidazoles_Induce_Apoptosis_in_Human_Breast_Cancer_Cells_by_Targeting_the_Oncogenic_PI3K_Akt_mTOR_Signaling_Pathway/3190366 <div><p>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 <i>in silico</i> 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.</p></div>