The Rational Design of Selective Benzoxazepin Inhibitors of the alpha-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326)

摘要

Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3K alpha have received substantial attention for their potential use in cancer therapy. Despite the particular attraction of targeting PI3K alpha, achieving selectivity for the inhibition of this isoform has proved challenging. Herein we report the discovery of inhibitors of PI3K alpha that have selectivity over the other class I isoforms and all other kinases tested. In GDC-0032 (3, taselisib), we previously minimized inhibition of PI3K beta relative to the other class I insoforms. Subsequently, we extended our efforts to identify PI3K alpha-specific inhibitors using PI3K alpha crystal structures to inform the design of benzoxazepin inhibitors with selectivity for PI3K alpha through interactions with a nonconserved residue. Several molecules selective for PI3K alpha relative to the other class I isoforms, as well as other kinases, were identified. Optimization of properties related to drug metabolism then culminated in the identification of the clinical candidate GDC-0326 (4).