Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity
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Yanfen Fang1,*, Yannan Kong1,*, Jianbei Xi1,*, Mengli Zhu1, Tong Zhu1, Tongtong Jiang1, Brendan Frett2, Wenhao Hu1, Hong-yu Li2, Mingliang Ma1, Xiongwen Zhang1
1Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
2Department of Pharmaceutical Science, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA
*These authors have contributed equally to this work
Xiongwen Zhang, email: firstname.lastname@example.org
Mingliang Ma, email: email@example.com
Hong-yu Li, email: firstname.lastname@example.org
Keywords: NEK2, mitosis, chromosome misalignment, cytokinesis failure, apoptosis
Received: August 04, 2016 Accepted: September 29, 2016 Published: October 15, 2016
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.
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