Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ–PI3Kδ Dual Inhibitors

An electronic density model was developed
and used to identify
a novel pyrrolotriazinone replacement for a quinazolinone, a commonly
used moiety to impart selectivity in inhibitors for PI3Kγ and
PI3Kδ. Guided by molecular docking, this new specificity piece
was then linked to the hinge-binding region of the inhibitor using
a novel cyclic moiety. Further structure–activity relationship
optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ–PI3Kδ
dual inhibitor with favorable drug metabolism and pharmacokinetic
properties in preclinical species.