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

被引：1
|
作者：
Galal, Kareem A. [1 ,2 ]
Kraemer, Andreas [3 ,4 ,5 ]
Strickland, Benjamin G. [1 ]
Smith, Jeffery L. [1 ]
Dickmander, Rebekah J. [2 ,6 ,7 ,8 ]
Moorman, Nathaniel J. [2 ,6 ,7 ]
Willson, Timothy M. [1 ,2 ]
机构：
[1] Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Struct Genom Consortium, Chapel Hill, NC 27599 USA
[2] Rapidly Emerging Antiviral Drug Dev Initiat READDI, Chapel Hill, NC 27599 USA
[3] Goethe Univ Frankfurt, Buchmann Inst Life Sci, Struct Genom Consortium, Max Von Laue Strabe 15, D-60438 Frankfurt, Germany
[4] Goethe Univ Frankfurt, Inst Pharmaceut Chem, Max Von Laue Strabe 9, D-60438 Frankfurt, Germany
[5] Frankfurt Canc Inst, Paul Ehrlich Str 42-44, D-60596 Frankfurt, Germany
[6] Univ North Carolina Chapel Hill, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA
[7] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[8] Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC 27599 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2024年 / 99卷
关键词：
A B S T R A C T; 2,6-DISUBSTITUTED PYRAZINES; KINASES; CK2;
D O I：
10.1016/j.bmcl.2024.129617
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
We report the synthesis of 2,6-disubstituted pyrazines as potent cell active CSNK2A inhibitors. 4 '-Carboxyphenyl '-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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页数：6
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