Synthesis and Biological Validation of a Harmine-based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor.

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ID: 92802
2020
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Abstract
Recently, our group identified that harmine is able to induce β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from lack of selectivity, both against other kinases and CNS off-targets, therefore, we sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets, while retaining human β-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human β-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for β-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2c is a much-improved in vivo lead candidate as compared to harmine, for the treatment of diabetes.
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kumar2020synthesisjournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Kumar, Kunal;Wang, Peng;Wilson, Jessica;Zlatanic, Victor;Berrouet, Cecilia;Khamrui, Susmita;Secor, Cody;Swartz, Ethan;Lazarus, Michael B;Sanchez, Roberto;Stewart, Andrew F;Garcia-Ocana, Adolfo;DeVita, Robert J;
Journal Journal of medicinal chemistry
Year 2020
DOI
10.1021/acs.jmedchem.9b01379
URL
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