Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor

Phosphoinositide-3-kinase (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 optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent bio...

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Published in:	Bioorganic & medicinal chemistry letters Vol. 22; no. 10; pp. 3460 - 3466
Main Authors:	Martínez González, Sonia, Hernández, Ana Isabel, Varela, Carmen, Rodríguez-Arístegui, Sonsoles, Lorenzo, Milagros, Rodríguez, Antonio, Rivero, Virginia, Martín, José Ignacio, Saluste, Carl Gustav, Ramos-Lima, Francisco, Cendón, Elena, Cebrián, David, Aguirre, Enara, Gomez-Casero, Elena, Albarrán, Maribel, Alfonso, Patricia, García-Serelde, Beatriz, Oyarzabal, Julen, Rabal, Obdulia, Mulero, Francisca, Gonzalez-Granda, Teresa, Link, Wolfgang, Fominaya, Jesús, Barbacid, Mariano, Bischoff, James R., Pizcueta, Pilar, Pastor, Joaquín
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 15-05-2012 Elsevier
Subjects:	Administration, Oral Biological and medical sciences Biological Availability Cancer treatment gene expression regulation growth retardation Humans Imidazoles - administration & dosage Imidazoles - pharmacokinetics Imidazoles - pharmacology Isoenzymes - antagonists & inhibitors Medical sciences mice mutation neoplasms pharmacokinetics Pharmacology. Drug treatments phosphatidylinositol 3-kinase Phosphatidylinositol 3-Kinases - antagonists & inhibitors phosphorylation PI3K inhibitors Positron-Emission Tomography Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology pyrazines Pyrazines - administration & dosage Pyrazines - pharmacokinetics Pyrazines - pharmacology signal transduction therapeutics Tomography, X-Ray Computed PI3K inhibitors Cancer treatment Antineoplastic agent Signal transduction Enzyme Transferases Oral administration Inhibitor Bioavailability Pharmacokinetics 1-Phosphatidylinositol 3-kinase
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Abstract	Phosphoinositide-3-kinase (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 optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKTSer473 phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-RasG12V oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition.
AbstractList	Phosphoinositide-3-kinase (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 optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKT(Ser473) phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition. Phosphoinositide-3-kinase (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 optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKTSer473 phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-RasG12V oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition. Phosphoinositide-3-kinase (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 optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKTSᵉʳ⁴⁷³ phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-Rasᴳ¹²ⱽ oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition.
Author	Rodríguez, Antonio Mulero, Francisca García-Serelde, Beatriz Ramos-Lima, Francisco Gonzalez-Granda, Teresa Pastor, Joaquín Varela, Carmen Martín, José Ignacio Rabal, Obdulia Pizcueta, Pilar Gomez-Casero, Elena Alfonso, Patricia Hernández, Ana Isabel Rodríguez-Arístegui, Sonsoles Oyarzabal, Julen Cebrián, David Lorenzo, Milagros Martínez González, Sonia Albarrán, Maribel Cendón, Elena Link, Wolfgang Rivero, Virginia Saluste, Carl Gustav Bischoff, James R. Aguirre, Enara Fominaya, Jesús Barbacid, Mariano
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organization: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain – sequence: 10 givenname: Francisco surname: Ramos-Lima fullname: Ramos-Lima, Francisco organization: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain – sequence: 11 givenname: Elena surname: Cendón fullname: Cendón, Elena organization: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain – sequence: 12 givenname: David surname: Cebrián fullname: Cebrián, David organization: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain – sequence: 13 givenname: Enara surname: Aguirre fullname: Aguirre, Enara organization: Experimental Therapeutics Programme, Spanish National Cancer Research 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Wolfgang organization: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain – sequence: 23 givenname: Jesús surname: Fominaya fullname: Fominaya, Jesús organization: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain – sequence: 24 givenname: Mariano surname: Barbacid fullname: Barbacid, Mariano organization: Molecular Onclology Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain – sequence: 25 givenname: James R. surname: Bischoff fullname: Bischoff, James R. organization: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain – sequence: 26 givenname: Pilar surname: Pizcueta fullname: Pizcueta, Pilar organization: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain – sequence: 27 givenname: Joaquín surname: Pastor fullname: Pastor, Joaquín email: jpastor@cnio.es organization: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain
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Keywords	PI3K inhibitors Cancer treatment Antineoplastic agent Signal transduction Enzyme Transferases Oral administration Inhibitor Bioavailability Pharmacokinetics 1-Phosphatidylinositol 3-kinase
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Snippet	Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human...
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SubjectTerms	Administration, Oral Biological and medical sciences Biological Availability Cancer treatment gene expression regulation growth retardation Humans Imidazoles - administration & dosage Imidazoles - pharmacokinetics Imidazoles - pharmacology Isoenzymes - antagonists & inhibitors Medical sciences mice mutation neoplasms pharmacokinetics Pharmacology. Drug treatments phosphatidylinositol 3-kinase Phosphatidylinositol 3-Kinases - antagonists & inhibitors phosphorylation PI3K inhibitors Positron-Emission Tomography Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology pyrazines Pyrazines - administration & dosage Pyrazines - pharmacokinetics Pyrazines - pharmacology signal transduction therapeutics Tomography, X-Ray Computed
Title	Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor
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