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A Dual Inhibitor of DYRK1A and GSK3β for β‐Cell Proliferation: Aminopyrazine Derivative GNF4877
Author(s) -
Liu Yahu A.,
Jin Qihui,
Ding Qiang,
Hao Xueshi,
Mo Tingting,
Yan Shanshan,
Zou Yefen,
Huang Zhihong,
Zhang Xiaoyue,
Gao Wenqi,
Wu Tom Y.H.,
Li Chun,
Bursalaya Badry,
Di Donato Michael,
Zhang YouQing,
Deaton Lisa,
Shen Weijun,
Taylor Brandon,
Kamireddy Anwesh,
Harb George,
Li Jing,
Jia Yong,
Schumacher Andrew M.,
Laffitte Bryan,
Glynne Richard,
Pan Shifeng,
McNamara Peter,
Molteni Valentina,
Loren Jon
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000183
Subject(s) - dyrk1a , cell growth , insulin , gsk 3 , cell , glycogen synthase , diabetes mellitus , kinase , chemistry , pharmacology , microbiology and biotechnology , biology , biochemistry , endocrinology
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.