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bioRxiv · 10.1101/2023.12.04.569845

Identification of 2-(4'-carboxyphenyl)-6-indolopyrazines as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3

Galal, K.·Kramer, A.·Strickland, B. G.·Smith, J. L.·Dickmander, R. J.·Moorman, N. J.·Willson, T. M.
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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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=60 SRC="FIGDIR/small/569845v2_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1b0a36corg.highwire.dtl.DTLVardef@1b940bdorg.highwire.dtl.DTLVardef@14953d9org.highwire.dtl.DTLVardef@11fd67a_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Galal, K., Kramer, A., Strickland, B. G., Smith, J. L., Dickmander, R. J., Moorman, N. J., Willson, T. M.. 2023-12-04. Identification of 2-(4'-carboxyphenyl)-6-indolopyrazines as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3. https://doi.org/10.1101/2023.12.04.569845

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