| Literature DB >> 32077280 |
Yahu A Liu1, Qihui Jin1, Yefen Zou1, Qiang Ding1, Shanshan Yan1, Zhicheng Wang1, Xueshi Hao1, Bao Nguyen1, Xiaoyue Zhang1, Jianfeng Pan1, Tingting Mo1, Kate Jacobsen1, Thanh Lam1, Tom Y-H Wu1, H Michael Petrassi1, Badry Bursulaya1, Michael DiDonato1, W Perry Gordon1, Bo Liu1, Janine Baaten1, Robert Hill1, Vân Nguyen-Tran1, Minhua Qiu1, You-Qing Zhang1, Anwesh Kamireddy1, Sheryll Espinola1, Lisa Deaton1, Sukwon Ha1, George Harb1, Yong Jia1, Jing Li1, Weijun Shen1, Andrew M Schumacher1, Karyn Colman1, Richard Glynne1, Shifeng Pan1, Peter McNamara1, Bryan Laffitte1, Shelly Meeusen1, Valentina Molteni1, Jon Loren1.
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).Entities:
Year: 2020 PMID： 32077280 DOI： 10.1021/acs.jmedchem.9b01624
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446