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This version was published on February 1, 2008
Journal of Biomolecular Screening, Vol. 13, No. 2, 128-134 (2008)
DOI: 10.1177/1087057107313763

Identification of Glucose-Dependent Insulin Secretion Targets in Pancreatic β Cells by Combining Defined-Mechanism Compound Library Screening and siRNA Gene Silencing

Weizhen Wu

Merck Research Laboratories, Rahway, NJ

Jin Shang

Merck Research Laboratories, Rahway, NJ

Yue Feng

Merck Research Laboratories, Rahway, NJ

Chris M. Thompson

Merck Research Laboratories, Rahway, NJ

Sarah Horwitz

Merck Research Laboratories, Rahway, NJ

John R. Thompson

Merck Research Laboratories, Rahway, NJ

Euan D. Macintyre

Merck Research Laboratories, Rahway, NJ

Nancy A. Thornberry

Merck Research Laboratories, Rahway, NJ

Kevin Chapman

Merck Research Laboratories, Rahway, NJ

Yun-Ping Zhou

Merck Research Laboratories, Rahway, NJ

Andrew D. Howard

Merck Research Laboratories, Rahway, NJ, Andrew_howard{at}merck.com

Jing Li

Merck Research Laboratories, Rahway, NJ, jing_li4{at}merck.com

Identification and validation of novel drug targets continues to be a major bottleneck in drug development, particularly for polygenic complex diseases such as type 2 diabetes. Here, the authors describe an approach that allows researchers to rapidly identify and validate potential drug targets by combining chemical tools and RNA interference technology. As a proof-of-concept study, the known mechanism Sigma LOPAC library was used to screen for glucose-dependent insulin secretion (GDIS) in INS-1 832/13 cells. In addition to several mechanisms that are known to regulate GDIS (such as cyclic adenosine monophosphate—specific phosphodiesterases, adrenoceptors, and Ca2+ channels), the authors find that several of the dopamine receptor (DRD) antagonists significantly enhance GDIS, whereas DRD agonists profoundly inhibit GDIS. Subsequent siRNA studies in the same cell line indicate that knockdown of DRD2 enhanced GDIS. Furthermore, selective DRD2 antagonists and agonists also enhance or suppress, respectively, GDIS in isolated rat islets. The data support that the approach described here offers a rapid and effective way for target identification and validation. (Journal of Biomolecular Screening 2008;128-134)

Key Words: type 2 diabetes • insulin secretion • compound library screen • siRNA


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