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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.