Pharmacologic characterization of SHR8443, a novel dual inhibitor of phosphatidylinositol 3-kinase and mammalian target of rapamycin.

ABSTRACT: Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in human cancer and contributes to resistance to antitumor therapy. Inhibition of key signaling proteins in this pathway therefore represents an attractive targeting strategy for cancer therapy. Here, we show that SHR8443, an imidazo [4,5-c] quinoline derivative, inhibited mammalian target of rapamycin (mTOR) kinase and PI3K, especially PI3Kα/δ/γ isoforms with picomolar potency, by binding to the ATP subunits of the respective enzymes. Inhibition of PI3K/AKT/mTOR signaling by SHR8443 induced G₁ phase arrest, autophagy and apoptosis, and resulted in broad anti-proliferative activity against a panel of cancer cells with different genetic backgrounds. Furthermore, SHR8443 overcame resistance to RAF/

SUBMITTER: Xie C 

PROVIDER: S-EPMC5746119 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature