TY - JOUR
T1 - PCC0208017, a novel small-molecule inhibitor of MARK3/MARK4, suppresses glioma progression in vitro and in vivo
AU - Li, Fangfang
AU - Liu, Zongliang
AU - Sun, Heyuan
AU - Li, Chunmei
AU - Wang, Wenyan
AU - Ye, Liang
AU - Yan, Chunhong
AU - Tian, Jingwei
AU - Wang, Hongbo
N1 - Funding Information:
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) and Key Research Project of Yantai ( 2019XDHZ102 , China).
Publisher Copyright:
© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences
PY - 2020/2
Y1 - 2020/2
N2 - 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, blood–brain 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.
AB - 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, blood–brain 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.
KW - Glioma
KW - MARK3
KW - MARK4
KW - Molecular docking
KW - PCC0208017
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U2 - 10.1016/j.apsb.2019.09.004
DO - 10.1016/j.apsb.2019.09.004
M3 - Article
AN - SCOPUS:85072842697
SN - 2211-3835
VL - 10
SP - 289
EP - 300
JO - Acta Pharmaceutica Sinica B
JF - Acta Pharmaceutica Sinica B
IS - 2
ER -