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A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Liu, Yahu, Jin, Qihui, Ding, Qiang, Hao, Xueshi, Mo, Tingting, Yan, Shanshan, Zou, Yefen, Huang, Zhihong, Zhang, Xiaoyue, Gao, Wenqi, Wu, Tom Y.-H., Li, Chun, Bursulaya, Badry, DiDonato, Michael, Zhang, You-Qing, Deaton, Lisa, Shen, Weijun, Taylor, Brandon, Kamireddy, Anwesh , Harb, George , Li, Jing, Jia, Yong, Schumacher, Andrew, Laffitte, Bryan , Glynne, Richard , Pan, Shifeng, McNamara, Peter, Molteni, Valentina and Loren, Jon (2020) A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877. ChemMedChem, 15. ISSN 18607187


Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.

Item Type: Article
Keywords: aminopyrazines diabetes inhibitors kinases pancreatic beta-cell proliferation synthases
Date Deposited: 04 Aug 2020 00:45
Last Modified: 04 Aug 2020 00:45


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