Discovery of a Phosphoinositide 3‑Kinase (PI3K) β/δ Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template by Targeting Nonconserved Asp856

Phosphoinositide 3-kinase (PI3K)
β signaling is required to sustain cancer cell growth in which
the tumor suppressor phosphatase and tensin homolog (PTEN) has been
deactivated. This manuscript describes the discovery, optimization,
and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors
in which PI3Kβ potency was built in a PI3Kδ-selective
template. This work led to the discovery of a highly selective PI3Kβ/δ
inhibitor displaying excellent pharmacokinetic profile and efficacy
in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor
model.