Structure-Based Designof a Novel Series of Potent, Selective Inhibitors of the Class IPhosphatidylinositol 3-Kinases.

A highly selective series of inhibitors of the classI phosphatidylinositol3-kinases (PI3Ks) has been designed and synthesized. Starting fromthe dual PI3K/mTOR inhibitor 5, a structure-based approachwas used to improve potency and selectivity, resulting in the identificationof 54as a potent inhibitor of the class I PI3Ks withexcellent selectivity over mTOR, related phosphatidylinositol kinases,and a broad panel of protein kinases. Compound 54demonstrateda robust PD–PK relationship inhibiting the PI3K/Akt pathwayin vivo in a mouse model, and it potently inhibited tumor growth ina U-87 MG xenograft model with an activated PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]