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Selective DYRK1A inhibitor for the treatment of Type 1 Diabetes: Discovery of 6-azaindole derivative GNF2133

Liu, Yahu, Zou, Yefen, Yan, Shanshan, Wang, Zhicheng, Hao, Xueshi, Nguyen, Bao, Zhang, Xiaoyue, Bursulaya, Badry, DiDonato, Michael, Gordon, William, Baaten, Janine, Hill, Robert, Qiu, Minhua, Zhang, You-Qing, Espinola, Sheryll, Deaton, Lisa, Ha, Sukwon, Jia, Yong, Schumacher, Andrew, Colman, Karyn, Pan, Shifeng, McNamara, Peter, Meeusen, Shelly, Molteni, Valentina, Loren, Jon, Jin, Qihui , Ding, Qiang , Pan, Jianfeng , Mo, Tingting , Jacobsen, Kate , Lam, Thanh , Wu, Tom Y.-H. , Petrassi, Hank Michael , Liu, Bo , Nguyen-Tran, Vân , Kamireddy, Anwesh , Harb, George , Li, Jing , Shen, Weijun , Glynne, Richard and Laffitte, Bryan (2020) Selective DYRK1A inhibitor for the treatment of Type 1 Diabetes: Discovery of 6-azaindole derivative GNF2133. Journal of Medicinal Chemistry, 63 (6). pp. 2958-2973. ISSN 0022-26231520-4804


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).

Item Type: Article
Keywords: DYRK1A DYRK1B GSK3B beta cell diabetes beta cell proliferation DYRK1A inhibitor DYRK1B inhibitor GSK3B inhibitor Kinase inhibitor
Date Deposited: 21 Apr 2020 00:45
Last Modified: 21 Apr 2020 00:45


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