Small Molecule Insulin Mimetic

[Rcjohnsen]

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Discovery of a Small Molecule Insulin Mimetic with Antidiabetic Activity in
Mice 

Bei Zhang, 1*  Gino Salituro, 2  Deborah Szalkowski, 1  Zhihua Li, 1  Yan
Zhang, 2  Inmaculada Royo, 4  Dolores Vilella, 4  Maria Teresa Díez, 4 
Fernando Pelaez, 4  Caroline Ruby, 2  Richard L. Kendall, 5  Xianzhi Mao, 5 
Patrick Griffin, 3  Jimmy Calaycay, 3  Juleen R. Zierath, 6  James V. Heck, 2 
Roy G. Smith, 1  David E. Moller 1  
Insulin elicits a spectrum of biological responses by binding to its cell
surface receptor. In a screen for small molecules that activate the human
insulin receptor tyrosine kinase, a nonpeptidyl fungal metabolite (L-783,281)
was identified that acted as an insulin mimetic in several biochemical and
cellular assays. The compound was selective for insulin receptor versus
insulin-like growth factor I (IGFI) receptor and other receptor tyrosine
kinases. Oral administration of L-783,281 to two mouse models of diabetes
resulted in significant lowering in blood glucose levels. These results
demonstrate the feasibility of discovering novel insulin receptor activators
that may lead to new therapies for diabetes.  

Sci 284:974-977 7 May 99