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

Abstract

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 (T 1/2 > 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.

Identification of Novel PI3Kα Inhibitor Against Gastric Cancer: QSAR-, Molecular Docking–, and Molecular Dynamics Simulation–Based Analysis

“…Molecular Dynamics simulations of the screened complexes with the lowest binding energies were performed using GROMACS 5.0 [23]. The CHARMM 36 force eld was applied for topology development of the screened and reference ligands [24].…”