title: Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation.
abstract: PPARγ is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARγ, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARγ drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARγ.
authors: Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Jang Hyun
authors: JH
authors: Choi
authors: Alexander S
authors: AS
authors: Banks
authors: Theodore M
authors: TM
authors: Kamenecka
authors: Scott A
authors: SA
authors: Busby
authors: Michael J
authors: MJ
authors: Chalmers
authors: Naresh
authors: N
authors: Kumar
authors: Dana S
authors: DS
authors: Kuruvilla
authors: Youseung
authors: Y
authors: Shin
authors: Yuanjun
authors: Y
authors: He
authors: John B
authors: JB
authors: Bruning
authors: David P
authors: DP
authors: Marciano
authors: Michael D
authors: MD
authors: Cameron
authors: Dina
authors: D
authors: Laznik
authors: Michael J
authors: MJ
authors: Jurczak
authors: Stephan C
authors: SC
authors: Schürer
authors: Dušica
authors: D
authors: Vidović
authors: Gerald I
authors: GI
authors: Shulman
authors: Bruce M
authors: BM
authors: Spiegelman
authors: Patrick R
authors: PR
authors: Griffin
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D001826:Body Fluids / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors*; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008958:Models, Molecular; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects
chemical_list: C561901:(S)-4'-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-(1,1'-biphenyl)-2-carboxylic acid; C561902:(S)-4'-((5-(1-(4-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylic acid; D001713:Biphenyl Compounds; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D010768:Phosphoserine; C089946:2,4-thiazolidinedione; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse