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

Abstract

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
URI:	https://oak.novartis.com/id/eprint/40915