944804-72-2Relevant articles and documents
Azole-based inhibitors of AKT/PKB for the treatment of cancer
Zeng, Qingping,Allen, John G.,Bourbeau, Matthew P.,Wang, Xianghong,Yao, Guomin,Tadesse, Seifu,Rider, James T.,Yuan, Chester C.,Hong, Fang-Tsao,Lee, Matthew R.,Zhang, Shiwen,Lofgren, Julie A.,Freeman, Daniel J.,Yang, Suijin,Li, Chun,Tominey, Elizabeth,Huang, Xin,Hoffman, Douglas,Yamane, Harvey K.,Fotsch, Christopher,Dominguez, Celia,Hungate, Randall,Zhang, Xiaoling
scheme or table, p. 1559 - 1564 (2010/06/16)
Through a combination of screening and structure-based rational design, we have discovered a series of N1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.
