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A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877 |
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| Authors: | Dr Yahu A Liu Dr Qihui Jin Qiang Ding Dr Xueshi Hao Tingting Mo Shanshan Yan Dr Yefen Zou Dr Zhihong Huang Xiaoyue Zhang Wenqi Gao Dr Tom Y-H Wu Chun Li Dr Badry Bursalaya Dr Michael Di Donato Dr You-Qing Zhang Lisa Deaton Dr Weijun Shen Dr Brandon Taylor Anwesh Kamireddy Dr George Harb Dr Jing Li Dr Yong Jia Dr Andrew M Schumacher Dr Bryan Laffitte Dr Richard Glynne Dr Shifeng Pan Dr Peter McNamara Dr Valentina Molteni Dr Jon Loren |
| Affiliation: | Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, CA 92121 USA |
| 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. |
| Keywords: | aminopyrazines diabetes inhibitors kinases pancreatic beta-cell proliferation synthases |