Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2

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  • Ong H.W
    • Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Yang X
    • Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Smith J.L
    • Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Taft-Benz S
    • School of Medicine, Department of Genetics
  • Howell S
    • Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Dickmander R.J
    • School of Medicine, Department of Microbiology and Immunology
  • Havener T.M
    • Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Sanders M.K
    • School of Medicine, Department of Genetics
  • Brown J.W
    • Other Affiliation: Takeda Development Center Americas, Inc
  • Couñago R.M
    • Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Chang E
    • Other Affiliation: Takeda Development Center Americas, Inc
  • Krämer A
    • Other Affiliation: Structural Genomics Consortium (SGC), Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
  • Moorman N.J
    • School of Medicine, Department of Microbiology and Immunology
  • Heise M
    • School of Medicine, Department of Genetics
  • Axtman A.D
    • Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Drewry D.H
    • Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Willson T.M
    • Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
Abstract
  • The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold possess outstanding potency and selectivity for CSNK2, but bioavailability and metabolic stability are often challenging. By strategically installing a fluorine atom on an electron-rich phenyl ring of a previously characterized inhibitor 1, we discovered compound 2 as a promising lead compound with improved in vivo metabolic stability. Compound 2 maintained excellent cellular potency against CSNK2, submicromolar antiviral potency, and favorable solubility, and was remarkably selective for CSNK2 when screened against 192 kinases across the human kinome. We additionally present a co-crystal structure to support its on-target binding mode. In vivo, compound 2 was orally bioavailable, and demonstrated modest and transient inhibition of CSNK2, although antiviral activity was not observed, possibly attributed to its lack of prolonged CSNK2 inhibition.
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  • Article
License
  • Attribution 4.0 International
Journal title
  • Molecules
Journal volume
  • 29
Journal issue
  • 17
Language
  • English
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  • Publisher
ISSN
  • 1420-3049
Publisher
  • Multidisciplinary Digital Publishing Institute (MDPI)

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