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

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

Abstract

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
URI: https://oak.novartis.com/id/eprint/42466

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