Discovery of 3-Quinazolin-4(3)-on-3-yl-2,-dimethylpropanamides as Orally Active and Selective PI3Kα Inhibitors.

Phosphoinositide 3-kinases (PI3Ks) mediate a series of events related to cell growth, proliferation, survival, and differentiation. Overexpression of PI3Ks can lead to the dysregulation of cell homeostasis and cause tumorigenesis. In this study, rationally designed compounds were investigated as PI3Kα-selective inhibitors. Our efforts culminated in the discovery of a series of quinazolin-4(3)-one derivatives with 2-substituted--methylpropanamide substitutions as PI3Kα-selective inhibitors. The best compound, , has PI3Kα enzymatic and cellular IC values of 1.8 and 12.1 nM, respectively. It exhibits biochemical selectivities for PI3Kα over PI3Kβ/δ/γ of 150/7.72/7.67-fold and cellular selectivities of 115/15.1/>826-fold, respectively. Compound is 59% orally bioavailable with a dose-normalized AUC of 3090 nM. These effects translated into in vivo conditions, as significantly time- and dose-dependently inhibited phosphorylation of Akt in BT-474 subcutaneous xenograft mice and inhibited tumor growth.