Details

Autor(en) / Beteiligte

• Liu, Yahu A
• Jin, Qihui
• Zou, Yefen
• Ding, Qiang
• Yan, Shanshan
• Wang, Zhicheng
• Hao, Xueshi
• Nguyen, Bao
• Zhang, Xiaoyue
• Pan, Jianfeng
• Mo, Tingting
• Jacobsen, Kate
• Lam, Thanh
• Wu, Tom Y.-H
• Petrassi, H. Michael
• Bursulaya, Badry
• DiDonato, Michael
• Gordon, W. Perry
• Liu, Bo
• Baaten, Janine
• Hill, Robert
• Nguyen-Tran, Vân
• Qiu, Minhua
• Zhang, You-Qing
• Kamireddy, Anwesh
• Espinola, Sheryll
• Deaton, Lisa
• Ha, Sukwon
• Harb, George
• Jia, Yong
• Li, Jing
• Shen, Weijun
• Schumacher, Andrew M
• Colman, Karyn
• Glynne, Richard
• Pan, Shifeng
• McNamara, Peter
• Laffitte, Bryan
• Meeusen, Shelly
• Molteni, Valentina
• Loren, Jon

Titel

Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6‑Azaindole Derivative GNF2133

Ist Teil von

• Journal of medicinal chemistry, 2020-03, Vol.63 (6), p.2958-2973

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human β-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).