1428249-59-5Relevant articles and documents
Discovery of 4-aminopyrimidine analogs as highly potent dual P70S6K/Akt inhibitors
Bankston, Donald,Chen, Xiaoling,Clark, Anderson,DeSelm, Lizbeth,Dutt, Vikram,Gardberg, Anna,Goutopoulos, Andreas,Head, Jared,Huck, Bayard R.,Jackson, Jennifer,Jiang, Xuliang,Johnson, Theresa,Jones, Christopher C. V.,Lan, Ruoxi,Lin, Jing,Ma, Jianguo,Machl, Andreas,Mochalkin, Igor,Neagu, Constantin,Qiu, Hui,Santos, Dusica,Sherer, Brian,Syed, Sakeena,Tian, Hui,Wilker, Erik,Xiao, Yufang
, (2021/09/13)
Activation of the PI3K/Akt/mTOR kinase pathway is associated with human cancers. A dual p70S6K/Akt inhibitor is sufficient to inhibit strong tumor growth and to block negative impact of the compensatory Akt feedback loop activation. A scaffold docking strategy based on an existing quinazoline carboxamide series identified 4-aminopyrimidine analog 6, which showed a single-digit nanomolar and a micromolar potencies in p70S6K and Akt enzymatic assays. SAR optimization improved Akt enzymatic and p70S6K cellular potencies, reduced hERG liability, and ultimately discovered the promising candidate 37, which exhibited with a single digit nanomolar value in both p70S6K and Akt biochemical assays, and hERG activities (IC50 = 17.4 μM). This agent demonstrated dose-dependent efficacy in inhibiting mice breast cancer tumor growth and covered more than 90% pS6 inhibition up to 24 h at a dose of 200 mg/kg po.
