Abstract
Casein kinase 1δ/ε have been identified as promising therapeutic target for oncology application, including breast and brain cancer. Here, we described our continued efforts in optimization of a lead series of purine scaffold inhibitors that led to identification of two new CK1δ/ε inhibitors 17 and 28 displaying low nanomolar values in antiproliferative assays against the human MDA-MB-231 triple negative breast cancer cell line and have physical, in vitro and in vivo pharmacokinetic properties suitable for use in proof of principle animal xenograft studies against human cancers.
Keywords:
Breast cancer; Casein kinase 1 delta and epsilon; Inhibitor; Kinase; Structure-activity relationship.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Binding Sites
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Casein Kinase 1 epsilon / antagonists & inhibitors*
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Casein Kinase 1 epsilon / metabolism
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Casein Kinase Idelta / antagonists & inhibitors*
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Casein Kinase Idelta / metabolism
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Catalytic Domain
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Cell Line, Tumor
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Female
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Half-Life
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Molecular Docking Simulation
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Permeability / drug effects
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Rats
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Structure-Activity Relationship
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Transplantation, Heterologous
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Triple Negative Breast Neoplasms / drug therapy
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Triple Negative Breast Neoplasms / metabolism
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Triple Negative Breast Neoplasms / pathology
Substances
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Protein Kinase Inhibitors
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Casein Kinase 1 epsilon
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Casein Kinase Idelta