Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity
| Autor: | Yanfen Fang, Yannan Kong, Jianbei Xi, Mengli Zhu, Tong Zhu, Tongtong Jiang, Brendan Frett, Wenhao Hu, Hong-yu Li, Mingliang Ma, Xiongwen Zhang |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Cell Survival Biology chromosome misalignment 03 medical and health sciences Mice Stomach Neoplasms Cell Line Tumor medicine Animals Humans NIMA-Related Kinases Gastrointestinal cancer Pharmaceutical sciences Kinase activity Mitosis Protein Kinase Inhibitors Cell Proliferation mitosis cytokinesis failure Dose-Response Relationship Drug apoptosis medicine.disease HCT116 Cells Xenograft Model Antitumor Assays In vitro Gene Expression Regulation Neoplastic Molecular Docking Simulation NEK2 030104 developmental biology Oncology Apoptosis Immunology Cancer research Phosphorylation Colorectal Neoplasms Cytokinesis Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Yanfen Fang 1, * , Yannan Kong 1, * , Jianbei Xi 1, * , Mengli Zhu 1 , Tong Zhu 1 , Tongtong Jiang 1 , Brendan Frett 2 , Wenhao Hu 1 , Hong-yu Li 2 , Mingliang Ma 1 , Xiongwen Zhang 1 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China 2 Department of Pharmaceutical Science, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA * These authors have contributed equally to this work Correspondence to: Xiongwen Zhang, email: xwzhang@sat.ecnu.edu.cn Mingliang Ma, email: mlma@brain.ecnu.edu.cn Hong-yu Li, email: hongyuli@pharmacy.arizona.edu Keywords: NEK2, mitosis, chromosome misalignment, cytokinesis failure, apoptosis Received: August 04, 2016 Accepted: September 29, 2016 Published: October 15, 2016 ABSTRACT NEK2 is a conserved mitotic regulator critical for cell cycle progression. Aberrant expression of NEK2 has been found in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. In the present study, we have identified a novel compound MBM-5, which was found to bind to NEK2 with high affinity by docking simulations study. MBM-5 potently inhibited NEK2 kinase activity in vitro in a concentration-dependent manner. MBM-5 also suppressed cellular NEK2 kinase activity, as evidenced by the decreased phosphorylation of its substrate Hec1 on S165 in a concentration- and time-dependent manner. This inhibition impeded mitotic progression by inducing chromosome segregation defects and cytokinesis failure; therefore leading to accumulation of cells with ≥4N DNA content, which finally underwent apoptosis. More importantly, MBM-5 treatment effectively suppressed the tumor growth of human gastric and colorectal cancer cells xenografts. Taken together, we demonstrated that MBM-5 effectively inhibited the kinase activity of NEK2 and showed a potential application in anti-cancer treatment regimens. |
| Databáze: | OpenAIRE |
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