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Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133.

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Author information

Affiliations

  • 1. Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
      Authors
    • Liu YA 1
    • Jin Q 1
    • Zou Y 1
    • Ding Q 1
    • Yan S 1
    • Wang Z 1
    • Hao X 1
    • Nguyen B 1
    • Zhang X 1
    • Pan J 1
    • Mo T 1
    • Jacobsen K 1
    • Lam T 1
    • Wu TY 1
    • Petrassi HM 1
    • Bursulaya B 1
    • DiDonato M 1
    • Gordon WP 1
    • Liu B 1
    • Baaten J 1
    • Hill R 1
    • Nguyen-Tran V 1
    • Qiu M 1
    • Zhang YQ 1
    • Kamireddy A 1
    • Espinola S 1
    • Deaton L 1
    • Ha S 1
    • Harb G 1
    • Jia Y 1
    • Li J 1
    • Shen W 1
    • Schumacher AM 1
    • Colman K 1
    • Glynne R 1
    • Pan S 1
    • McNamara P 1
    • Laffitte B 1
    • Meeusen S 1
    • Molteni V 1
    • Loren J 1
    (41 authors)

ORCIDs linked to this article

Journal of Medicinal Chemistry, 20 Feb 2020, 63(6):2958-2973
https://doi.org/10.1021/acs.jmedchem.9b01624 PMID: 32077280 

Abstract 

Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human β-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).

Full text links 

Read article at publisher's site: https://doi.org/10.1021/acs.jmedchem.9b01624

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Funding 

Funders who supported this work.

Genomics Institute of the Novartis Research Foundation

    JDRF (1)