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).
Subject(s)
Imidazoles/chemistry , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Pyrazines/chemistry , TOR Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cytochromes/metabolism , Disease Models, Animal , Half-Life , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Mice , Mice, Inbred BALB C , Microsomes, Liver/metabolism , Neoplasms/drug therapy , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , TOR Serine-Threonine Kinases/metabolism , Transplantation, HeterologousABSTRACT
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.
