Discovery of Novel Phosphoinositide-3-Kinase α Inhibitors with High Selectivity, Excellent Bioavailability, and Long-Acting Efficacy for Gastric Cancer

Phosphoinositide-3-kinase (PI3K) overexpressed in many
tumors is
a promising target for cancer therapy. However, due to toxicity from
the ubiquitous expression of PI3K in many tissues, the development
of PI3K inhibitors with high selectivity and low toxicity has become
an urgent need for tumor treatment. Herein, based on the HipHop, we designed and synthesized a series of 6-(4,6-dimorpholino-1,3,5-triazin-2-yl)­benzo­[d]­oxazol-2-amine derivatives as potent, selective, and long-acting
PI3Kα inhibitors. Compound 27 was determined with
potent PI3Kα inhibitory activity (IC50 = 4.4 nM),
which exhibited excellent selectivity for homologous PI3K enzymes
and a 370 kinome panel. Meanwhile, 27 featured favorable
stability (T1/2 > 10 h) and high bioavailability
(130%). Importantly, compound 27 exerted great antigastric
cancer activity in vivo when combined with taxol.
Collectively, these characteristics suggested 27 to be
a promising PI3K agent for cancer treatment.