Structure-based discovery of new maternal embryonic leucine zipper kinase inhibitors
| Autor: | Xin Long, Lei Zhong, Qi Fu, Jin-ku Bao, Shu Zhou, Kai Chen, Xiao-Juan Jiang, Guo-Bo Li, Hui Li, Lin Luo |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell Antineoplastic Agents Protein Serine-Threonine Kinases Biochemistry Maternal embryonic leucine zipper kinase Focal adhesion 03 medical and health sciences 0302 clinical medicine Cell Movement Cell Line Tumor Drug Discovery medicine Humans Neoplasm Invasiveness Physical and Theoretical Chemistry Protein kinase A Protein Kinase Inhibitors Chemistry Kinase Organic Chemistry Cancer medicine.disease Cell biology 030104 developmental biology medicine.anatomical_structure Focal Adhesion Kinase 1 030220 oncology & carcinogenesis Cancer cell Phosphorylation Signal Transduction |
| Zdroj: | Organic & Biomolecular Chemistry. 16:1489-1495 |
| ISSN: | 1477-0539 1477-0520 |
| Popis: | Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and plays a key functional role in various cancer cells. Although MELK may not be a cancer addiction target, the development of specific MELK inhibitors would provide useful chemical tools for synthetic lethal investigation. Herein, we identified several hit compounds using a customized structure-based virtual screening, among which compounds 4 and 16 showed the most potent inhibition to MELK with IC50 values of 3.52 μM and 178.3 nM, respectively. In vitro cell-based assays revealed that 16 has no effect on the growth of various types of cancer cells, but has the potential to inhibit cancer cell migration and invasion. Western blotting analyses revealed that 16 suppresses the phosphorylation of focal adhesion kinase (FAK), a downstream molecule of MELK, which is a key kinase in regulating cancer cell migration and invasion. |
| Databáze: | OpenAIRE |
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