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Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Jan 01; Vol. 28 (1), pp. 115193. Date of Electronic Publication: 2019 Nov 11. - Publication Year :
- 2020
-
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.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Binding Sites
Cell Proliferation drug effects
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 metabolism
Protein Kinase Inhibitors pharmacology
Protein Serine-Threonine Kinases antagonists & inhibitors
Protein Structure, Tertiary
Protein-Tyrosine Kinases antagonists & inhibitors
Small Molecule Libraries metabolism
Small Molecule Libraries pharmacology
Structure-Activity Relationship
Dyrk Kinases
Protein Kinase Inhibitors chemistry
Protein Serine-Threonine Kinases metabolism
Protein-Tyrosine Kinases metabolism
Small Molecule Libraries chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 28
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31757680
- Full Text :
- https://doi.org/10.1016/j.bmc.2019.115193