Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight

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• 作者：B. Barry Touré ; John Giraldes ; Troy Smith ; Elizabeth R. Sprague ; Yaping Wang ; Simon Mathieu ; Zhuoliang Chen ; Yuji Mishina ; Yun Feng ; Yan Yan-Neale ; Subarna Shakya ; Dongshu Chen ; Matthew Meyer ; David Puleo ; J. Tres Brazell ; Christopher Straub ; David Sage ; Kirk Wright ; Yanqiu Yuan ; Xin Chen ; Jose Duca ; Sean Kim ; Li Tian ; Eric Martin ; Kristen Hurov ; Wenlin Shao
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4711-4723
• 全文大小：662K
• 年卷期：0
• ISSN：1520-4804

文摘

MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.