Abstract
Phosphoinositide-3-kinases (PI3K) are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. PI3K is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the rapid identification of ETP-46992, within 2-aminocarbonyl imidazo [1,2-a] pyrazine series, with suitable pharmacokinetic (PK) properties that allows the establishment of mechanism of action and efficacy in vivo studies. ETP-46992 showed tumor growth inhibition in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation and in tumor xenograft models with PI3K pathway deregulated (BT474).
Copyright © 2012 Elsevier Ltd. All rights reserved.
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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Apoptosis / drug effects
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Cell Line, Tumor
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Cytochromes / metabolism
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Disease Models, Animal
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Half-Life
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry*
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Imidazoles / pharmacokinetics
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Mice
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Mice, Inbred BALB C
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Microsomes, Liver / metabolism
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Neoplasms / drug therapy
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use
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Pyrazines / chemical synthesis
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Pyrazines / chemistry*
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Pyrazines / pharmacokinetics
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
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Transplantation, Heterologous
Substances
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Cytochromes
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ETP-46992
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Imidazoles
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyrazines
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TOR Serine-Threonine Kinases