Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast-cancer subtype associated with poor prognosis and high relapse rates. Monopolar spindle 1 kinase (MPS1) is an apical dual-specificity protein kinase that is over-expressed in TNBC. We herein report a highly selective MPS1 inhibitor based on a 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile scaffold. Our lead optimization was guided by key X-ray crystal structure analysis. In vivo evaluation of candidate (9) is shown to effectively mitigate human TNBC cell proliferation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Binding Sites
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Breast Neoplasms / drug therapy
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Breast Neoplasms / pathology
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Design*
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Female
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Half-Life
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Humans
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Mice
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Mice, Inbred ICR
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Molecular Docking Simulation
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / therapeutic use
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / metabolism
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Pyrimidines / chemistry*
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Pyrimidines / metabolism
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Pyrimidines / therapeutic use
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Pyrroles / chemistry*
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Pyrroles / metabolism
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Pyrroles / therapeutic use
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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Cell Cycle Proteins
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Protein Kinase Inhibitors
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Pyrimidines
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Pyrroles
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Pyrrolo(2,3-d)pyrimidine
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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TTK protein, human