Li Fangfang, Liu Zongliang, Sun Heyuan, Li Chunmei, Wang Wenyan, Ye Liang, Yan Chunhong, Tian Jingwei, Wang Hongbo
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai 264005, China.
Department of Clinical Medicine, Binzhou Medical College, Yantai 256603, China.
Acta Pharm Sin B. 2020 Feb;10(2):289-300. doi: 10.1016/j.apsb.2019.09.004. Epub 2019 Sep 18.
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. 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 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.
胶质瘤是所有脑恶性肿瘤中最常见的原发性颅内肿瘤，微管亲和力调节激酶（MARKs）已成为胶质瘤潜在的药物靶点。在此，我们报告一种新型的MARK3和MARK4双重小分子抑制剂，命名为PCC0208017。PCC0208017强烈抑制针对MARK3和MARK4的激酶活性，并显著降低三种胶质瘤细胞系的增殖。该化合物减弱了胶质瘤细胞的迁移、侵袭及血管生成。分子机制研究表明，PCC0208017降低了Tau蛋白的磷酸化水平，破坏了微管动力学，并诱导细胞周期阻滞于G2/M期。在胶质瘤模型中，PCC0208017显示出强大的抗肿瘤活性、血脑屏障通透性及良好的口服药代动力学特征。分子对接研究表明，PCC0208017对MARK3和MARK4具有高结合亲和力。综上所述，我们的研究首次描述了新型MARK3/MARK4抑制剂PCC0208017可能是一种有前景的治疗胶质瘤的先导化合物。
