title: Rapid identification of ETP-46992, orally bioavailable PI3K inhibitor, selective versus mTOR.
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).
authors: Experimental Therapeutics Programme, Spanish National Cancer Research Centre, C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
authors: Sonia
authors: S
authors: Martínez González
authors: Ana Isabel
authors: AI
authors: Hernández
authors: Carmen
authors: C
authors: Varela
authors: Milagros
authors: M
authors: Lorenzo
authors: Francisco
authors: F
authors: Ramos-Lima
authors: Elena
authors: E
authors: Cendón
authors: David
authors: D
authors: Cebrián
authors: Enara
authors: E
authors: Aguirre
authors: Elena
authors: E
authors: Gomez-Casero
authors: M I
authors: MI
authors: Albarrán
authors: Patricia
authors: P
authors: Alfonso
authors: Beatriz
authors: B
authors: García-Serelde
authors: Genoveva
authors: G
authors: Mateos
authors: Julen
authors: J
authors: Oyarzabal
authors: Obdulia
authors: O
authors: Rabal
authors: Francisca
authors: F
authors: Mulero
authors: Teresa
authors: T
authors: Gonzalez-Granda
authors: Wolfgang
authors: W
authors: Link
authors: Jesús
authors: J
authors: Fominaya
authors: Mariano
authors: M
authors: Barbacid
authors: James R
authors: JR
authors: Bischoff
authors: Pilar
authors: P
authors: Pizcueta
authors: Carmen
authors: C
authors: Blanco-Aparicio
authors: Joaquín
authors: J
authors: Pastor
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003580:Cytochromes / Q000378:metabolism; D004195:Disease Models, Animal; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D003580:Cytochromes; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D058570:TOR Serine-Threonine Kinases; C576474:ETP-46992