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

• Ngôn ngữ: eng
• Ký hiệu phân loại: 541.3 Miscellaneous topics in physical chemistry
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2016
• Mô tả vật lý: Size: p. 4711-4723 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260877
• Chủ đề: 1. 37 inorganic, organic, physical, and analytical chemistry; 2. 60 applied life sciences; 3. Cancer; 4. Cells; 5. Inhibition; 6. Inhibitors; 7. Peptides and proteins

Tóm tắt

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. Here, these novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.