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
The serine/threonine Pim 1 kinase is an oncogene whose expression is deregulated in several human cancers. Overexpression of Pim 1 facilitates cell cycle progression and suppresses apoptosis. Hence pharmacologic inhibitors of Pim 1 are of therapeutic interest for cancer. ETP-45299 is a potent and selective inhibitor of Pim 1 that inhibits the phosphorylation of Bad and 4EBP1 in cells and suppresses the proliferation of several non-solid and solid human tumor cell lines. The combination of the PI3K inhibitor GDC-0941 with ETP-45299 was strongly synergistic in MV-4-11 AML cells, indicating that the combination of selective Pim kinase inhibitors and PI3K inhibitor could have clinical benefit.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Leukemia, Myeloid, Acute , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Pyridazines/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Drug Synergism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Immunoblotting , Indazoles/pharmacology , Leukemia, Myeloid, Acute/metabolism , Pyridazines/chemistry , Sulfonamides/pharmacologyABSTRACT
Mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1 and MNK2) phosphorylate the oncogene eIF4E on serine 209. This phosphorylation has been reported to be required for its oncogenic activity. To investigate if pharmacological inhibition of MNK1 could be useful for the treatment of cancers, we pursued a comprehensive virtual screening approach to rapidly identify pharmacological tools for target validation and to find optimal starting points for a plausible medicinal chemistry project. A collection of 1236 compounds, selected from a library of 42 168 compounds and a database of 18.8 million structures, were assayed. Of the identified hits, 26 were found to have IC(50) values less than 10 µM (2.10% hit rate). The most potent compound had an IC(50) value of 117 nM, and 73.1% of these hits were fragments. The hits were characterized by a high ligand efficiency (0.32-0.52 kcal/mol per heavy atom). Ten different chemical scaffolds were represented, giving a chemotype/hit ratio of 0.38.
