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

Paul A Allegretti; Timothy M Horton; Yassan Abdolazimi; Hannah P Moeller; Benjamin Yeh; Matthew Caffet; Guillermina Michel; Mark Smith; Justin P Annes

doi:10.1016/j.bmc.2019.115193

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. Epub 2019 Nov 11.

Authors

Paul A Allegretti¹, Timothy M Horton², Yassan Abdolazimi³, Hannah P Moeller⁴, Benjamin Yeh³, Matthew Caffet⁵, Guillermina Michel³, Mark Smith⁵, Justin P Annes⁶

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cell Proliferation / drug effects
Dyrk Kinases
Humans
Insulin / metabolism
Insulin-Secreting Cells / cytology
Insulin-Secreting Cells / drug effects
Insulin-Secreting Cells / metabolism
Kinetics
Molecular Docking Simulation
Naphthyridines / chemical synthesis
Naphthyridines / chemistry
Naphthyridines / pharmacology
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism*
Protein Structure, Tertiary
Protein-Tyrosine Kinases / antagonists & inhibitors
Protein-Tyrosine Kinases / metabolism*
Small Molecule Libraries / chemistry*
Small Molecule Libraries / metabolism
Small Molecule Libraries / pharmacology
Structure-Activity Relationship

Substances

Insulin
Naphthyridines
Protein Kinase Inhibitors
Small Molecule Libraries
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding