title: Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor.
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 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.
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez González
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Hernández
authors.forename: Carmen
authors.initials: C
authors.lastname: Varela
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Rodríguez-Arístegui
authors.forename: Milagros
authors.initials: M
authors.lastname: Lorenzo
authors.forename: Antonio
authors.initials: A
authors.lastname: Rodríguez
authors.forename: Virginia
authors.initials: V
authors.lastname: Rivero
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Martín
authors.forename: Carl Gustav
authors.initials: CG
authors.lastname: Saluste
authors.forename: Francisco
authors.initials: F
authors.lastname: Ramos-Lima
authors.forename: Elena
authors.initials: E
authors.lastname: Cendón
authors.forename: David
authors.initials: D
authors.lastname: Cebrián
authors.forename: Enara
authors.initials: E
authors.lastname: Aguirre
authors.forename: Elena
authors.initials: E
authors.lastname: Gomez-Casero
authors.forename: Maribel
authors.initials: M
authors.lastname: Albarrán
authors.forename: Patricia
authors.initials: P
authors.lastname: Alfonso
authors.forename: Beatriz
authors.initials: B
authors.lastname: García-Serelde
authors.forename: Julen
authors.initials: J
authors.lastname: Oyarzabal
authors.forename: Obdulia
authors.initials: O
authors.lastname: Rabal
authors.forename: Francisca
authors.initials: F
authors.lastname: Mulero
authors.forename: Teresa
authors.initials: T
authors.lastname: Gonzalez-Granda
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Link
authors.forename: Jesús
authors.initials: J
authors.lastname: Fominaya
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
authors.forename: James R
authors.initials: JR
authors.lastname: Bischoff
authors.forename: Pilar
authors.initials: P
authors.lastname: Pizcueta
authors.forename: Joaquín
authors.initials: J
authors.lastname: Pastor
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014057:Tomography, X-Ray Computed
chemical_list: C574806:ETP-46321; D007093:Imidazoles; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011719:Pyrazines