| Literature DB >> 22520259 |
Sonia Martínez González1, Ana Isabel Hernández, Carmen Varela, Sonsoles Rodríguez-Arístegui, Milagros Lorenzo, Antonio Rodríguez, Virginia Rivero, José Ignacio Martín, Carl Gustav Saluste, Francisco Ramos-Lima, Elena Cendón, David Cebrián, Enara Aguirre, Elena Gomez-Casero, Maribel Albarrán, Patricia Alfonso, Beatriz García-Serelde, Julen Oyarzabal, Obdulia Rabal, Francisca Mulero, Teresa Gonzalez-Granda, Wolfgang Link, Jesús Fominaya, Mariano Barbacid, James R Bischoff, Pilar Pizcueta, Joaquín Pastor.
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.Entities:
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Year: 2012 PMID： 22520259 DOI： 10.1016/j.bmcl.2012.03.090
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823