Small-Molecule Inducer of β Cell Proliferation Identified by High-Throughput Screening

• Published in: Journal of the American Chemical Society 2013-02, Vol.135 (5), p.1669-1672
• Main Authors: Shen, Weijun, Tremblay, Matthew S, Deshmukh, Vishal A, Wang, Weidong, Filippi, Christophe M, Harb, George, Zhang, You-qing, Kamireddy, Anwesh, Baaten, Janine E, Jin, Qihui, Wu, Tom, Swoboda, Jonathan G, Cho, Charles Y, Li, Jing, Laffitte, Bryan A, McNamara, Peter, Glynne, Richard, Wu, Xu, Herman, Ann E, Schultz, Peter G
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Humans; Islets of Langerhans - cytology; Islets of Langerhans - drug effects; Mice; Molecular Structure; Molecular Weight; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacology
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja309304m

The identification of factors that promote β cell proliferation could ultimately move type 1 diabetes treatment away from insulin injection therapy and toward a cure. We have performed high-throughput, cell-based screens using rodent β cell lines to identify molecules that induce proliferation of β cells. Herein we report the discovery and characterization of WS6, a novel small molecule that promotes β cell proliferation in rodent and human primary islets. In the RIP-DTA mouse model of β cell ablation, WS6 normalized blood glucose and induced concomitant increases in β cell proliferation and β cell number. Affinity pulldown and kinase profiling studies implicate Erb3 binding protein-1 and the IκB kinase pathway in the mechanism of action of WS6.