Identification of 4-(6-((2-methoxyphenyl)amino)pyrazin-2-yl)benzoic acids as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3
Copyright © 2024 Elsevier Ltd. All rights reserved..
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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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:99 |
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| Enthalten in: |
Bioorganic & medicinal chemistry letters - 99(2024) vom: 01. Feb., Seite 129617 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Galal, Kareem A [VerfasserIn] |
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Date Completed 06.02.2024 Date Revised 06.02.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Dec 05;:. - PMID 38106118 Citation Status MEDLINE |
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| doi: |
10.1016/j.bmcl.2024.129617 |
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| PPN (Katalog-ID): |
NLM36689918X |
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| 245 | 1 | 0 | |a Identification of 4-(6-((2-methoxyphenyl)amino)pyrazin-2-yl)benzoic acids as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3 |
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| 500 | |a Date Revised 06.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2023 Dec 05;:. - PMID 38106118 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier Ltd. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Benzoates |2 NLM | |
| 650 | 7 | |a Pyrazines |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 700 | 1 | |a Krämer, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Strickland, Benjamin G |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Jeffery L |e verfasserin |4 aut | |
| 700 | 1 | |a Dickmander, Rebekah J |e verfasserin |4 aut | |
| 700 | 1 | |a Moorman, Nathaniel J |e verfasserin |4 aut | |
| 700 | 1 | |a Willson, Timothy M |e verfasserin |4 aut | |
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