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

Yahu A LiuQihui JinQiang DingXueshi HaoTingting MoShanshan YanYefen ZouZhihong HuangXiaoyue ZhangWenqi GaoTom Y-H WuChun LiBadry BursalayaMichael Di DonatoYou-Qing ZhangLisa DeatonWeijun ShenBrandon TaylorAnwesh KamireddyGeorge HarbJing LiYong JiaAndrew M SchumacherBryan LaffitteRichard GlynneShifeng PanPeter McNamaraValentina MolteniJon Loren
Published in: ChemMedChem (2020)
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.
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