MBX-102/JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema

Francine M. Gregoire, Fang Zhang, Holly J. Clarke, Thomas A. Gustafson, Dorothy D. Sears, Svetlana Favelyukis, James Lenhard, Dennis Rentzeperis, L. Edward Clemens, Yi Mu, Brian E. Lavan

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68 Scopus citations

Abstract

MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)-γ that is differentiated from the TZDs structurally, mechanistically, preclinically and clinically. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR-γ agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-γ target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-γ agonists, MBX-102 displays differential interactions with the PPAR-γ ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR-γ or α/γ agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-γ modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-γ side effects and may represent the next generation insulin sensitizer.

Original languageEnglish (US)
Pages (from-to)975-988
Number of pages14
JournalMolecular Endocrinology
Volume23
Issue number7
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Gregoire, F. M., Zhang, F., Clarke, H. J., Gustafson, T. A., Sears, D. D., Favelyukis, S., Lenhard, J., Rentzeperis, D., Clemens, L. E., Mu, Y., & Lavan, B. E. (2009). MBX-102/JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema. Molecular Endocrinology, 23(7), 975-988. https://doi.org/10.1210/me.2008-0473