Introduction of pyrrolidineoxy or piperidineamino group at the 4-position of quinazoline leading to novel quinazoline-based phosphoinositide 3-kinase delta (PI3K?) inhibitors.

ABSTRACT: Phosphoinositide 3-kinase Delta (PI3K?) plays a key role in B-cell signal transduction and inhibition of PI3K? was confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Herein, we reported a novel series of 4-pyrrolidineoxy or 4-piperidineamino substituted quinazolines, showing potent PI3K? inhibitory activities. Among these compounds, 12d, 14b and 14c demonstrated higher potency against PI3K? with the half maximal inhibitory concentration (IC50) values of 4.5, 3.0, and 3.9?nM, respectively, which were comparable to idelalisib (IC50?=?2.7?nM). The further PI3K isoforms selectivity evaluation showed that compounds 12d, 14b and 14c have excellent PI3K? selectivity over PI3K?, PI3K?, and PI3K?. Moreover, compounds 12d, 14b and 14c also displayed different anti-proliferative profiles against a panel of four human B cell lines including Ramos, Raji, RPMI-8226, and SU-DHL-6. The molecular docking simulation indicated several key hydrogen bonding interactions were formed. This study suggests the introduction of pyrrolidineoxy or piperidineamino groups into the 4-position of quinazoline leads to new potent and selective PI3K? inhibitors.

SUBMITTER: Xin M 

PROVIDER: S-EPMC6009876 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature