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Identification of 4-(6-((2-methoxyphenyl)amino)pyrazin-2-yl)benzoic acids as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3.
Galal, Kareem A; Krämer, Andreas; Strickland, Benjamin G; Smith, Jeffery L; Dickmander, Rebekah J; Moorman, Nathaniel J; Willson, Timothy M.
Afiliación
  • Galal KA; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Krämer A; Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA.
  • Strickland BG; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Max-von-Laue-Strabe 15, Frankfurt 60438, Germany.
  • Smith JL; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strabe 9, Frankfurt 60438, Germany.
  • Dickmander RJ; Frankfurt Cancer Institute, Paul-Ehrlich-Straße 42-44, Frankfurt 60596, Germany.
  • Moorman NJ; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Willson TM; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
bioRxiv ; 2023 Dec 05.
Article en En | MEDLINE | ID: mdl-38106118
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos