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Science 7 May 1999:
Vol. 284. no. 5416, pp. 974 - 977
DOI: 10.1126/science.284.5416.974
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Reports

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, 1dagger 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.

1 Department of Molecular Endocrinology,
2 Department of Natural Product Drug Discovery,
3 Department of Molecular Diversity and Design, Merck Research Laboratories, R80W250, Post Office Box 2000, Rahway, NJ 07065, USA.
4 Centro de Investigación Básica, Merck, Sharp & Dohme de España, S. A. Josefa Valcárcel 38, Madrid 28027, Spain.
5 Department of Cancer Research, Merck Research Laboratories, Post Office Box 4, West Point, PA 19486, USA.
6 Department of Clinical Physiology, Karolinska Hospital, Karolinska Institute, S-171 76 Stockholm, Sweden.
*   To whom correspondence should be addressed. E-mail: bei_zhang{at}merck.com

dagger    Present address: Huffington Center on Aging and Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, M-320, Houston, TX 77030, USA.

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