2. Academic Validation
  3. Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2

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

  • Molecules. 2024 Sep 2;29(17):4158. doi: 10.3390/molecules29174158.
Han Wee Ong 1 2,  Xuan Yang 1 2,  Jeffery L Smith 2,  Sharon Taft-Benz 1 3,  Stefanie Howell 2,  Rebekah J Dickmander 1 4 5 6,  Tammy M Havener 2,  Marcia K Sanders 1 3,  Jason W Brown 7,  Rafael M Couñago 2 8,  Edcon Chang 7,  Andreas Krämer 9,  Nathaniel J Moorman 1 4 5,  Mark Heise 1 3,  Alison D Axtman 1 2,  David H Drewry 1 2 5,  Timothy M Willson 1 2
Affiliations

Affiliations

  • 1 Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA.
  • 2 Structural Genomics Consortium (SGC) and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4 Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 5 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 6 Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 7 Takeda Development Center Americas, Inc., San Diego, CA 92121, USA.
  • 8 Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), University of Campinas, Campinas 13083-886, SP, Brazil.
  • 9 Structural Genomics Consortium (SGC), Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
PMID: 39275006 DOI: 10.3390/molecules29174158
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.

Keywords

CSNK2; SARS-CoV-2; antiviral; fluorination; pyrazolo[1,5-a]pyrimidine; β-coronavirus.

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