title: TM-25659 enhances osteogenic differentiation and suppresses adipogenic differentiation by modulating the transcriptional co-activator TAZ.
abstract: OBJECTIVE
  The transcriptional co-activator with PDZ-binding motif (TAZ) is characterized as a transcriptional modulator of mesenchymal stem cell differentiation into osteoblasts and adipocytes. Moreover, increased TAZ activity in the nucleus enhances osteoblast differentiation and suppresses adipocyte development by interacting with runt-related transcription factor 2 (RUNX2) and PPARγ, respectively. Therefore, it would be of interest to identify low MW compounds that modulate nuclear TAZ activity.
  
  
  METHODS
  High-throughput screening was performed using a library of low MW compounds in order to identify TAZ modulators that enhance nuclear TAZ localization. The effects and molecular mechanisms of a TAZ modulator have been characterized in osteoblast and adipocyte differentiation.
  
  
  RESULTS
  We identified 2-butyl-5-methyl-6-(pyridine-3-yl)-3-[2'-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine] (TM-25659) as a TAZ modulator. TM-25659 enhanced nuclear TAZ localization in a dose-dependent manner and attenuated PPARγ-mediated adipocyte differentiation by facilitating PPARγ suppression activity of TAZ. In addition, TAZ-induced RUNX2 activity activation was further increased in osteoblasts, causing increased osteoblast differentiation. Accordingly, TM-25659 suppressed bone loss in vivo and decreased weight gain in an obesity model. After oral administration, TM-25659 had a favourable pharmacokinetic profile.
  
  
  CONCLUSIONS
  TM-25659 stimulated nuclear TAZ localization and thus caused TAZ to suppress PPARγ-dependent adipogenesis and enhance RUNX2-induced osteoblast differentiation in vitro and in vivo. Our data suggest that TM-25659 could be beneficial in the control of obesity and bone loss.
authors.affiliation: College of Pharmacy and Division of Life and Pharmaceutical Sciences and Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul Korea.
authors.forename: E J
authors.initials: EJ
authors.lastname: Jang
authors.forename: H
authors.initials: H
authors.lastname: Jeong
authors.forename: J O
authors.initials: JO
authors.lastname: Kang
authors.forename: N J
authors.initials: NJ
authors.lastname: Kim
authors.forename: M S
authors.initials: MS
authors.lastname: Kim
authors.forename: S H
authors.initials: SH
authors.lastname: Choi
authors.forename: S E
authors.initials: SE
authors.lastname: Yoo
authors.forename: J H
authors.initials: JH
authors.lastname: Hong
authors.forename: M A
authors.initials: MA
authors.lastname: Bae
authors.forename: E S
authors.initials: ES
authors.lastname: Hwang
mesh_terms: D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D047495:PPAR gamma / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries; D013777:Tetrazoles / Q000494:pharmacology*; D015534:Trans-Activators; D015430:Weight Gain / Q000187:drug effects / Q000235:genetics
chemical_list: C572937:2-butyl-5-methyl-6-(pyridine-3-yl)-3-(2'-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl)-3H-imidazo(4,5-b)pyridine; D048868:Adaptor Proteins, Signal Transducing; D019086:Bridged Bicyclo Compounds, Heterocyclic; D050659:Core Binding Factor Alpha 1 Subunit; D047495:PPAR gamma; D054852:Small Molecule Libraries; D013777:Tetrazoles; D015534:Trans-Activators; C517794:Wwtr1 protein, mouse