Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133 PMID: 32077280

ADC Targets in Oncology

2026-04-10

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

J Med Chem. 2020 Mar 26;63(6):2958-2973. doi: 10.1021/acs.jmedchem.9b01624.

Yahu A Liu ¹ , Qihui Jin ¹ , Yefen Zou ¹ , Qiang Ding ¹ , Shanshan Yan ¹ , Zhicheng Wang ¹ , Xueshi Hao ¹ , Bao Nguyen ¹ , Xiaoyue Zhang ¹ , Jianfeng Pan ¹ , Tingting Mo ¹ , Kate Jacobsen ¹ , Thanh Lam ¹ , Tom Y-H Wu ¹ , H Michael Petrassi ¹ , Badry Bursulaya ¹ , Michael DiDonato ¹ , W Perry Gordon ¹ , Bo Liu ¹ , Janine Baaten ¹ , Robert Hill ¹ , Vân Nguyen-Tran ¹ , Minhua Qiu ¹ , You-Qing Zhang ¹ , Anwesh Kamireddy ¹ , Sheryll Espinola ¹ , Lisa Deaton ¹ , Sukwon Ha ¹ , George Harb ¹ , Yong Jia ¹ , Jing Li ¹ , Weijun Shen ¹ , Andrew M Schumacher ¹ , Karyn Colman ¹ , Richard Glynne ¹ , Shifeng Pan ¹ , Peter McNamara ¹ , Bryan Laffitte ¹ , Shelly Meeusen ¹ , Valentina Molteni ¹ , Jon Loren ¹

Affiliations

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).