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Molecular Endocrinology, doi:10.1210/me.2008-0473
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Molecular Endocrinology 23 (7): 975-988
Copyright © 2009 by The Endocrine Society

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 and Brian E. Lavan

Metabolex (F.M.G., H.J.C., L.E.C., Y.M., B.E.L.), Department of Biology, Hayward, Californaia 94545; Lilly Research Laboratories (F.Z.), Indianapolis, Indiana 46285; Pfizer, Inc. (T.A.G.), Groton, Connecticut 06340; Department of Medicine (D.D.S., S.F.), Division of Endocrinology and Metabolism, University of California, San Diego, California 92103; and Johnson & Johnson PRD (J.L., D.R.), Exton, Pennsylvania 19341

Address all correspondence and requests for reprints to: Dr. Brian Lavan, Department of Biology, Metabolex, 3876 Bay Center Place, Hayward, California 94545. E-mail: blavan{at}metabolex.com.

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)-{gamma} 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-{gamma} agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-{gamma} target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-{gamma} agonists, MBX-102 displays differential interactions with the PPAR-{gamma} 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-{gamma} or {alpha}/{gamma} agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-{gamma} modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-{gamma} side effects and may represent the next generation insulin sensitizer.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARγ
Coregulators:   TRAP220  |  PGC-1  |  CBP  |  SRC-1  |  GRIP1  |  NCOR  |  SMRT
Ligands:   Rosiglitazone





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Copyright © 2009 by The Endocrine Society