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

  • Bioorg Med Chem Lett. 2012 May 15;22(10):3460-6. doi: 10.1016/j.bmcl.2012.03.090.
Sonia Martínez González  1 ,  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
Affiliations
  • 1. Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
PMID: 22520259 DOI: 10.1016/j.bmcl.2012.03.090
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.

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