Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 17, Pages 7687-7699Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00658
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Funding
- NIH Grant NIDDK [R01DK DK105015-01-A1, UC4 DK104211, P-30 DK 020541, JDRF 2-SRA-2017 514]
- Icahn School of Medicine Seed Fund [0285-3980]
- Scientific Computing at the Icahn School of Medicine at Mount Sinai
- NIDDK
- NIDDK Human Ilseet Research Network
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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 beta-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 beta-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 beta-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 beta-cell proliferation at doses of 3-30 mu M, and compound 2-2 showed improved kinase selectivity as compared to harmine.
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