Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases

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• 作者：Adrian L. Smith ; Noel D. D鈥橝ngelo ; Yunxin Y. Bo ; Shon K. Booker ; Victor J. Cee ; Brad Herberich ; Fang-Tsao Hong ; Claire L. M. Jackson ; Brian A. Lanman ; Longbin Liu ; Nobuko Nishimura ; Liping H. Pettus ; Anthony B. Reed ; Seifu Tadesse ; Nuria A. Tamayo ; Ryan P. Wurz ; Kevin Yang ; Kristin L. Andrews ; Douglas A. Whittington ; John D. McCarter ; Tisha San Miguel ; Leeanne Zalameda ; Jian Jiang ; Raju Subramanian ; Erin L. Mullady ; Sean Caenepeel ; Daniel J. Freeman ; Ling Wang ; Nancy Zhang ; Tian Wu ; Paul E. Hughes ; Mark H. Norman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5188-5219
• 全文大小：1004K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD鈥揚K relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.