Abstract
High-throughput screening for the induction of a luciferase reporter gene in a thrombopoietin (TPO)-responsive cell line resulted in the identification of 4-diazo-3-hydroxy-1-naphthalenesulfonic acids as TPO mimics. Modification of the core structure and adjustment of unwanted functionality resulted in the development of (5-oxo-1,5-dihydropyrazol-4-ylidene)hydrazines which exhibited efficacies equivalent to those of TPO in several cell-based assays designed to measure thrombopoietic activity. Furthermore, these compounds elicited biochemical responses in TPO-receptor-expressing cells similar to those in TPO itself, including kinase activation and protein phosphorylation. Potencies for the best compounds were high for such low molecular weight compounds (MW < 500) with EC(50) values in the region of 1-20 nM.
MeSH terms
-
Animals
-
Azo Compounds / chemical synthesis*
-
Azo Compounds / chemistry
-
Azo Compounds / pharmacology
-
Cell Division
-
Cell Line
-
Drug Evaluation, Preclinical
-
Electrophoretic Mobility Shift Assay
-
Enzyme Activation
-
Genes, Reporter
-
Hydrazines / chemical synthesis*
-
Hydrazines / chemistry
-
Hydrazines / pharmacology
-
Luciferases / genetics
-
Luciferases / metabolism
-
Megakaryocytes / drug effects*
-
Mice
-
Molecular Mimicry
-
Molecular Weight
-
Naphthalenesulfonates / chemical synthesis*
-
Naphthalenesulfonates / chemistry
-
Naphthalenesulfonates / pharmacology
-
Neoplasm Proteins*
-
Phosphorylation
-
Phosphotransferases / metabolism
-
Proto-Oncogene Proteins / metabolism
-
Pyrazoles / chemical synthesis*
-
Pyrazoles / chemistry
-
Pyrazoles / pharmacology
-
Receptors, Cytokine*
-
Receptors, Thrombopoietin
-
Structure-Activity Relationship
-
Thrombopoietin / chemistry*
-
Thrombopoietin / metabolism
Substances
-
Azo Compounds
-
Hydrazines
-
Naphthalenesulfonates
-
Neoplasm Proteins
-
Proto-Oncogene Proteins
-
Pyrazoles
-
Receptors, Cytokine
-
Receptors, Thrombopoietin
-
MPL protein, human
-
Thrombopoietin
-
Luciferases
-
Phosphotransferases