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Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo.

ABSTRACT: In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKT(S129), a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft.

SUBMITTER: Dowling JE

PROVIDER: S-EPMC4027246 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo.

Dowling James E JE Alimzhanov Marat M Bao Larry L Block Michael H MH Chuaqui Claudio C Cooke Emma L EL Denz Christopher R CR Hird Alex A Huang Shan S Larsen Nicholas A NA Peng Bo B Pontz Timothy W TW Rivard-Costa Caroline C Saeh Jamal Carlos JC Thakur Kumar K Ye Qing Q Zhang Tao T Lyne Paul D PD

ACS medicinal chemistry letters 20130703 8

In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKT(S129), a direct substrate of CK2, in vitro and in vivo, and e ...[more]

PMID: 24900749

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