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

Kareem A Galal; Andreas Krämer; Benjamin G Strickland; Jeffery L Smith; Rebekah J Dickmander; Nathaniel J Moorman; Timothy M Willson

doi:10.1016/j.bmcl.2024.129617

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 Feb 1:99:129617. doi: 10.1016/j.bmcl.2024.129617. Epub 2024 Jan 8.

Authors

Kareem A Galal¹, Andreas Krämer², Benjamin G Strickland³, Jeffery L Smith³, Rebekah J Dickmander⁴, Nathaniel J Moorman⁵, Timothy M Willson⁶

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: tim.willson@unc.edu.

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.

MeSH terms

Antiviral Agents / pharmacology
Benzoates*
Pyrazines* / pharmacology
Structure-Activity Relationship

Substances

Benzoates
Pyrazines
Antiviral Agents