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
  • 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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