AI Article Synopsis
- Modifications made to the 6-position helped enhance selectivity against another enzyme, PIM3, while still effectively inhibiting CSNK2A; a key compound showed strong inhibition at nanomolar levels.
- The final versions of these compounds also demonstrated the ability to inhibit viral replication, confirming their potential therapeutic applications based on their CSNK2A activity.
Article 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 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 , 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10723276 | PMC |
| http://dx.doi.org/10.1101/2023.12.04.569845 | DOI Listing |
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