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. Epub 2012 Mar 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Biological Availability
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology*
  • Isoenzymes / antagonists & inhibitors*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Positron-Emission Tomography
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazines / administration & dosage
  • Pyrazines / pharmacokinetics
  • Pyrazines / pharmacology*
  • Tomography, X-Ray Computed

Substances

  • ETP-46321
  • Imidazoles
  • Isoenzymes
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrazines