Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: Synthesis and SAR studies

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• 作者：Xiaodong Lin ; Jeremy M. Murray ; Alice C. Rico ; Michael X. Wang ; Daniel T. Chu ; Yasheen Zhou ; Merci Del Rosario ; Susan Kaufman ; Sylvia Ma ; Eric Fang et al.
• 关键词：Protein kinase B/AKT ; kinase inhibitor ; Substituted pyrimidine ; Cancer
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2006
• 出版时间：15 August 2006
• 年：2006
• 卷：16
• 期：16
• 页码：4163-4168
• 全文大小：282 K

文摘

A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. SAR studies resulted in potent inhibitors of AKT with IC₅₀ values as low as single digit nanomolar as represented by compound 2aa. Compound 2aa showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed.