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A Simple Method to Identify Kinases That Regulate Embryonic Stem Cell Pluripotency by High-throughput Inhibitor Screening
Published on: May 12, 2017
Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and
B Barry Touré1, John Giraldes1, Troy Smith1
1Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Abstract:
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.
Insights
Researchers developed novel MELK kinase inhibitors that block cancer cell growth. A unique fluorine-induced hydrophobic collapse enhanced potency, leading to well-tolerated drug candidates for further evaluation in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Maternal embryonic leucine-zipper kinase (MELK) is crucial in tumorigenesis.
- MELK regulates cell cycle and its inhibition halts growth in specific breast cancer types.
- Previous studies linked MELK to cell cycle regulation and growth inhibition via genetic depletion.
Purpose of the Study:
- To discover and optimize novel MELK inhibitors.
- To validate that these inhibitors mimic MELK knockdown effects in cellular models.
- To investigate a novel fluorine-induced hydrophobic collapse mechanism for enhanced potency.
Main Methods:
- Discovery and optimization of novel MELK inhibitors (compounds 8a and 8b).
- Utilizing short hairpin ribonucleic acid (shRNA) for MELK knockdown validation.
- Structural analysis to identify fluorine-induced hydrophobic collapse.
- In vitro and in vivo pharmacokinetic and tolerability studies.
Main Results:
- Compounds 8a and 8b effectively inhibited MELK kinase.
- Inhibitors recapitulated cellular effects of MELK knockdown.
- A novel fluorine-induced hydrophobic collapse resulted in a 20-fold increase in potency.
- Inhibitors demonstrated high in vivo exposure and good tolerability.
Conclusions:
- Novel MELK inhibitors (8a and 8b) were successfully developed.
- These inhibitors show promise for treating cancers dependent on MELK.
- The identified fluorine-induced hydrophobic collapse is a key mechanism for drug potency enhancement.
- The compounds are suitable for further in vivo efficacy studies.
