Identification of 4-(6-((2-methoxyphenyl)amino)pyrazin-2-yl)benzoic acids as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3

  • Bioorg Med Chem Lett. 2024 Jan 8:99:129617. doi: 10.1016/j.bmcl.2024.129617.
Kareem A Galal  1 ,  Andreas Krämer  2 ,  Benjamin G Strickland  3 ,  Jeffery L Smith  3 ,  Rebekah J Dickmander  4 ,  Nathaniel J Moorman  5 ,  Timothy M Willson  6
Affiliations
  • 1. Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA.
  • 2. Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Max-von-Laue-Strabe 15, Frankfurt 60438, Germany; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strabe 9, Frankfurt 60438, Germany; Frankfurt Cancer Institute, Paul-Ehrlich-Straße 42-44, Frankfurt 60596, Germany.
  • 3. Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4. Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 5. Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 6. Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA. Electronic address: [email protected].
PMID: 38199328 DOI: 10.1016/j.bmcl.2024.129617
Abstract

We report the synthesis of 2,6-disubstituted pyrazines as potent cell active CSNK2A inhibitors. 4'-Carboxyphenyl was found to be the optimal 2-pyrazine substituent for CSNK2A activity, with little tolerance for additional modification. At the 6-position, modifications of the 6-isopropylaminoindazole substituent were explored to improve selectivity over PIM3 while maintaining potent CSNK2A inhibition. The 6-isopropoxyindole analogue 6c was identified as a nanomolar CSNK2A inhibitor with 30-fold selectivity over PIM3 in cells. Replacement of the 6-isopropoxyindole by isosteric ortho-methoxy anilines, such as 7c, generated analogues with selectivity for CSNK2A over PIM3 and improved the kinome-wide selectivity. The optimized 2,6-disubstituted pyrazines showed inhibition of viral replication consistent with their CSNK2A activity.

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