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

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

Potent and Selective Inhibitors of CK2 Kinase Identified through Structure-Guided Hybridization

In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo­[1,5-<i>a</i>]­pyrimidine hits identified by kinase-focused subset screening as starting points for the structure-based design of conformationally constrained 6-acetamido-indole inhibitors of CK2. The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation <i>in vitro</i> are described