Original articles
Fangfang Li, Zongliang Liu, Heyuan Sun, Chunmei Li, Wenyan Wang, Liang Ye, Chunhong Yan, Jingwei Tian, Hongbo Wang. PCC0208017, a novel small-molecule inhibitor of MARK3/MARK4, suppresses glioma progression in vitro and in vivo[J]. Acta Pharmaceutica Sinica B, 2020, 10(2): 289-300

PCC0208017, a novel small-molecule inhibitor of MARK3/MARK4, suppresses glioma progression in vitro and in vivo
Fangfang Lia, Zongliang Liua, Heyuan Suna, Chunmei Lia, Wenyan Wanga, Liang Yeb, Chunhong Yana,c, Jingwei Tiana, Hongbo Wanga
a School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation(Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China;
b Department of Clinical Medicine, Binzhou Medical College, Yantai 256603, China cGRU Cancer Center, Augusta University, Augusta, GA 30912, USA
Gliomas are the most common primary intracranial neoplasms among all brain malignancies, and the microtubule affinity regulating kinases (MARKs) have become potential drug targets for glioma. Here, we report a novel dual small-molecule inhibitor of MARK3 and MARK4, designated as PCC0208017. In vitro, PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4, and strongly reduced proliferation in three glioma cell lines. This compound attenuated glioma cell migration, glioma cell invasion, and angiogenesis. Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau, disrupted microtubule dynamics, and induced a G2/M phase cell cycle arrest. In an in vivo glioma model, PCC0208017 showed robust anti-tumor activity, bloodebrain barrier permeability, and a good oral pharmacokinetic profile. Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4. Taken together, our study describes for the first time that PCC0208017, a novel MARK3/MARK4 inhibitor, might be a promising lead compound for treatment of glioma.
Key words:    Glioma    PCC0208017    MARK3    MARK4    Molecular docking   
Received: 2019-06-19     Revised: 2019-08-01
DOI: 10.1016/j.apsb.2019.09.004
Funds: We thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. This work was partially supported by National Science Foundation of China (NSFC, 81728020), Key Research Project of Shandong Province (2017GSF18177, China), Natural Science Foundation of Shandong Province (ZR2018LH025, China), The Science and Technology Support Program for Youth Innovation in Universities of Shandong (2019KJM009), Key Research Project of Yantai (2019XDHZ102, China) and Taishan Scholar Project.
Corresponding author: Jingwei Tian, Hongbo Wang     Email:YTUpharmlab@163.com;hongbowangyt@gmail.com
Author description:
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Fangfang Li
Zongliang Liu
Heyuan Sun
Chunmei Li
Wenyan Wang
Liang Ye
Chunhong Yan
Jingwei Tian
Hongbo Wang

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