2. Academic Validation
  3. Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization

Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization

  • Bioorg Med Chem. 2020 Jan 1;28(1):115193. doi: 10.1016/j.bmc.2019.115193.
Paul A Allegretti 1,  Timothy M Horton 2,  Yassan Abdolazimi 3,  Hannah P Moeller 4,  Benjamin Yeh 3,  Matthew Caffet 5,  Guillermina Michel 3,  Mark Smith 5,  Justin P Annes 6
Affiliations

Affiliations

  • 1 Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
  • 2 Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA; Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
  • 3 Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA.
  • 4 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA; Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA.
  • 5 Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
  • 6 Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA. Electronic address: Jannes@stanford.edu.
PMID: 31757680 DOI: 10.1016/j.bmc.2019.115193
Abstract

Small molecule stimulation of β-cell regeneration has emerged as a promising therapeutic strategy for diabetes. Although chemical inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is sufficient to enhance β-cell replication, current lead compounds have inadequate cellular potency for in vivo application. Herein, we report the clinical stage anti-cancer kinase inhibitor OTS167 as a structurally novel, remarkably potent DYRK1A inhibitor and inducer of human β-cell replication. Unfortunately, OTS167's target promiscuity and cytotoxicity curtails utility. To tailor kinase selectivity towards DYRK1A and reduce cytotoxicity we designed a library of fifty-one OTS167 derivatives based upon a modeled structure of the DYRK1A-OTS167 complex. Indeed, derivative characterization yielded several leads with exceptional DYRK1A inhibition and human β-cell replication promoting potencies but substantially reduced cytotoxicity. These compounds are the most potent human β-cell replication-promoting compounds yet described and exemplify the potential to purposefully leverage off-target activities of advanced stage compounds for a desired application.

Keywords

Diabetes; Dual-specificity tyrosine-regulated kinase 1A (DYRK1A); Medicinal chemistry; β-cell regeneration; β-cell replication.

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