l-Aminoacyl-triazine Derivatives Are Isoform-Selective PI3Kβ Inhibitors That Target Nonconserved Asp862 of PI3Kβ

摘要: A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified as potent and isoform-selective inhibitors PI3Kβ. The compounds showed selectivity stereochemistry with l-amino acyl preferring PI3Kβ, while their d-congeners favored PI3Kδ. mechanistic basis this inhibition was studied using site-directed mutants. One Asp residue, D862, a critical participant in binding to PI3Kβ-selective inhibitors, distinguishing class from other reported inhibitors. show strong cellular Akt phosphorylation growth PTEN-deficient MD-MBA-468 cells.