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- W2886244301 abstract "DYRK1A has been implicated as an important drug target in various therapeutic areas, including neurological disorders and oncology. DYRK1A has more recently been shown to be involved in pathways regulating human β-cell proliferation, thus making it a potential therapeutic target for both Type 1 and Type 2 diabetes. Our group, using a high-throughput phenotypic screen, identified harmine that is able to induce β-cell proliferation both in vitro and in vivo. Since harmine has suboptimal kinase selectivity, we sought to expand structure–activity relationships for harmine’s DYRK1A activity, to enhance selectivity, while retaining human β-cell proliferation capability. We carried out the optimization of the 1-position of harmine and synthesized 15 harmine analogues. Six compounds showed excellent DYRK1A inhibition with IC50 in the range of 49.5–264 nM. Two compounds, 2-2 and 2-8, exhibited excellent human β-cell proliferation at doses of 3–30 μM, and compound 2-2 showed improved kinase selectivity as compared to harmine." @default.
- W2886244301 created "2018-08-22" @default.
- W2886244301 creator A5008459770 @default.
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- W2886244301 creator A5049078993 @default.
- W2886244301 creator A5058318565 @default.
- W2886244301 date "2018-07-30" @default.
- W2886244301 modified "2023-10-16" @default.
- W2886244301 title "Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation" @default.
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- W2886244301 doi "https://doi.org/10.1021/acs.jmedchem.8b00658" @default.
- W2886244301 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6350255" @default.
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- W2886244301 hasPublicationYear "2018" @default.
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