ABSTRACT
Signal transducers and activators of transcription 5 (STAT5s) are crucial effectors of tyrosine kinase oncogenes in myeloid leukemias. Inhibition of STAT5 would contribute to reducing the survival of leukemic cells and also tackling their chemoresistance. In a first screening experiment, we identified hit 13 as able to inhibit STAT5 phosphorylation and leukemic cell growth. The synthesis of 18 analogues of 13 allowed us to identify one compound, 17f, as having the most potent antileukemic effect. 17f inhibited the growth of acute and chronic myeloid leukemia cells and the phosphorylation and transcriptional activity of STAT5. Importantly, 17f had minimal effects on bone marrow stromal cells that play vital functions in the microenvironment of hematopoietic and leukemic cells. We also demonstrated that 17f inhibits STAT5 but not STAT3, AKT, or Erk1/2 phosphorylation. These results suggest that 17f might be a new lead molecule targeting STAT5 signaling in myeloid leukemias.
Subject(s)
Antineoplastic Agents/chemistry , Indoles/chemistry , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myeloid, Acute/drug therapy , Quinolines/chemistry , STAT5 Transcription Factor/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Quinolines/chemical synthesis , Quinolines/pharmacology , Signal Transduction , Structure-Activity RelationshipABSTRACT
Type-2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance in the liver and peripheral tissues accompanied by a deficiency in pancreatic beta-cells. Since their discovery, three subtypes of peroxisome proliferator activated receptors have been identified, namely PPARalpha, PPARgamma and PPARbeta/(delta). In this study, we were interested in designing novel PPARgamma selective agonists and/or dual PPARalpha/gamma agonists. Based on the typical topology of synthetic PPAR agonists, we focused our design approach on using 4,4-dimethyl-1,2,3,4-tetrahydroquinoline as a novel cyclic scaffold with oxime and acidic head group structural variations.
Subject(s)
Oximes/chemistry , PPAR alpha/agonists , PPAR gamma/agonists , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Cell Line , Diabetes Mellitus, Type 2/drug therapy , Disease Models, Animal , Humans , Mice , PPAR alpha/metabolism , PPAR gamma/metabolism , Quinolines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Type-2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance in the liver and peripheral tissues accompanied by a defect in pancreatic beta-cell. Since their discovery three subtypes of Peroxisomes Proliferators Activated Receptors were identified namely PPARalpha, PPARgamma and PPARbeta/(delta). We were interested in designing novel PPARgamma selective agonists and/or dual PPARalpha/gamma agonists. Based on the typical topology of synthetic PPAR agonists, we focused our design approach on 4,4-dimethyl-1,2,3,4-tetrahydroquinoline as novel cyclic tail.
