Rapid identification of ETP-46992, orally bioavailable PI3K inhibitor, selective versus mTOR

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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-08, Vol.22 (16), p.5208-5214
Main Authors: Martínez González, Sonia, Hernández, Ana Isabel, Varela, Carmen, Lorenzo, Milagros, Ramos-Lima, Francisco, Cendón, Elena, Cebrián, David, Aguirre, Enara, Gomez-Casero, Elena, Albarrán, M.I., Alfonso, Patricia, García-Serelde, Beatriz, Mateos, Genoveva, Oyarzabal, Julen, Rabal, Obdulia, Mulero, Francisca, Gonzalez-Granda, Teresa, Link, Wolfgang, Fominaya, Jesús, Barbacid, Mariano, Bischoff, James R., Pizcueta, Pilar, Blanco-Aparicio, Carmen, Pastor, Joaquín
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Administration, Oral
Animal models
Animals
Apoptosis - drug effects
Biological and medical sciences
Cancer
Cancer treatment
Cell Line, Tumor
Cell migration
Cytochromes - metabolism
Differentiation
Disease Models, Animal
growth retardation
Half-Life
Humans
Imidazo [1,2-a] pyrazines
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacokinetics
in vivo studies
Lipid kinase
mechanism of action
Medical sciences
Mice
Mice, Inbred BALB C
Microsomes, Liver - metabolism
Mutation
neoplasms
Neoplasms - drug therapy
Pharmacokinetics
Pharmacology. Drug treatments
phosphatidylinositol 3-kinase
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphatidylinositol 3-Kinases - metabolism
PI3K inhibitors
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - therapeutic use
pyrazine
Pyrazines - chemical synthesis
Pyrazines - chemistry
Pyrazines - pharmacokinetics
Signal transduction
therapeutics
TOR protein
TOR Serine-Threonine Kinases - antagonists & inhibitors
TOR Serine-Threonine Kinases - metabolism
Transplantation, Heterologous
Tumors
Xenografts
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Summary: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-RasG12V oncogenic mutation and in tumor xenograft models with PI3K pathway deregulated (BT474).
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.06.093