期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 4, 期 8, 页码 800-805出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml400197u
关键词
CK2 kinase; pyrazolo[1,5-a]pyrimidine; matched molecular pair; oxetane
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.
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